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Major depressive disorder (MDD) is highly prevalent in youth. Conventional treatment paradigms primarily involve selective serotonin reuptake inhibitors (SSRIs) and psychotherapy, yet a significant proportion of this population exhibits treatment-resistant depression (TRD). In adults, interventional therapies like Electroconvulsive Therapy (ECT), repetitive Transcranial Magnetic Stimulation (rTMS), and ketamine have shown promise for TRD, but their comparative efficacy remains underexplored in Adolescent and pediatric population. This systematic review and meta-analysis aims to assess the relative effectiveness of ECT, rTMS, and ketamine in treating TRD among adolescents. Following PRISMA guidelines, we systematically searched databases for studies of ECT, rTMS, or ketamine for treatment-resistant depression in youth ages 10–24. Three reviewers independently screened for inclusion based on predefined criteria. Included observational and randomized controlled trials reported depression symptoms with measures like HDRS and MADRS in youth treated with ECT, rTMS, or ketamine. Two reviewers extracted data on interventions, patients, and depression symptom outcomes. Chance-adjusted inter-reviewer agreement was calculated. For meta-analysis, we pooled standardized mean differences (SMDs) in depression scores using random effects models and assessed heterogeneity with I2 statistics. Meta-analysis of 10 observational studies examined SMD in depression scores for treatment resistant depression patients treated with ECT, ketamine, or rTMS. Patients treated with ECT had a significantly lower SMD of 1.99 (95 % CI 0.92–3.05, p < 0.001) compared to baseline. Patients treated with ketamine also had a significantly lower SMD of 1.58 (95 % CI 1.04–2.12, p < 0.001). Patients treated with rTMS had the lowest SMD of 2.79 (95 % CI 0.79–4.80, p = 0.006). There was no significant difference between the three groups overall (p > 0.05). Comparative analysis between ECT and ketamine found no significant difference in SMD (p = 0.387). Comparison of ECT versus rTMS found a significant difference in SMD favoring rTMS (p = 0.004). Comparison of ketamine versus rTMS suggested a potential difference in SMD favoring rTMS (p = 0.058). In summary, rTMS resulted in significantly larger reductions in depression scores than ECT, and potentially larger reductions than ketamine. This meta-analysis illustrates the ability of rTMS, ECT, and ketamine to improve depression in youth. rTMS resulted in the largest improvements, highlighting its potential as a first-line treatment for pediatric treatment-resistant depression given its favorable side effect profile compared to ECT. Further research directly comparing these modalities is needed. • This systematic review assesses ECT, rTMS, and Ketamine for treating treatment-resistant depression in youth. • Standardized mean differences (SMDs) in depression scores for patients treated with ECT, ketamine, or rTMS were compared. • All 3 interventions significantly reduced depression symptoms with rTMS resulting in the largest SMD reduction of 2.79. • rTMS should be strongly considered for treatment-resistant depression in youth given its side effect profile and efficacy. [ABSTRACT FROM AUTHOR]

Background: A clinical tool to estimate the risk of treatment-resistant schizophrenia (TRS) in people with first-episode psychosis (FEP) would inform early detection of TRS and overcome the delay of up to 5 years in starting TRS medication. Aims: To develop and evaluate a model that could predict the risk of TRS in routine clinical practice. Method: We used data from two UK-based FEP cohorts (GAP and AESOP-10) to develop and internally validate a prognostic model that supports identification of patients at high-risk of TRS soon after FEP diagnosis. Using sociodemographic and clinical predictors, a model for predicting risk of TRS was developed based on penalised logistic regression, with missing data handled using multiple imputation. Internal validation was undertaken via bootstrapping, obtaining optimism-adjusted estimates of the model's performance. Interviews and focus groups with clinicians were conducted to establish clinically relevant risk thresholds and understand the acceptability and perceived utility of the model. Results: We included seven factors in the prediction model that are predominantly assessed in clinical practice in patients with FEP. The model predicted treatment resistance among the 1081 patients with reasonable accuracy; the model's C-statistic was 0.727 (95% CI 0.723–0.732) prior to shrinkage and 0.687 after adjustment for optimism. Calibration was good (expected/observed ratio: 0.999; calibration-in-the-large: 0.000584) after adjustment for optimism. Conclusions: We developed and internally validated a prediction model with reasonably good predictive metrics. Clinicians, patients and carers were involved in the development process. External validation of the tool is needed followed by co-design methodology to support implementation in early intervention services. [ABSTRACT FROM AUTHOR]

Background: When physician assisted dying (referred to as Medical Assistance in Dying or MAiD in this article) is available for individuals with mental disorders as the sole underlying medical condition (MD-SUMC), patients with borderline personality disorder (BPD) frequently request MAiD. Psychiatrists and other clinicians must be prepared to evaluate and manage these requests. Objectives: The purposes of this paper are to define when patients with BPD should be considered to have an irremediable, treatment resistant disorder and provide clinicians with an approach to assess and manage their patients with BPD making requests for MAiD. Methods: This perspective paper developed the authors' viewpoint by using a published, authoritative definition of irremediability and including noteworthy systematic and/or meta-analytic reviews related to the assessment of irremediability. Results: The clinician must be aware of the eligibility requirements for granting MAiD in their jurisdiction so that they can appropriately prepare themselves and their patients for the assessment process. The appraisal of the intolerability of the specific person's suffering comes from having an extensive dialogue with the patient; however, the assessment of whether the patient has irremediable BPD should be more objectively and reliably determined. A systematic approach to the assessment of irremediability of BPD is reviewed in the context of the disorder's severity, treatment resistance and irreversibility. Conclusion: In addition to characterizing irremediability, this paper also addresses the evaluation and management of suicide risk for patients with BPD undergoing the MAiD assessment process. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of concomitant use of benzodiazepines on the efficacy of repetitive transcranial magnetic stimulation (rTMS) in patients with treatment-resistant major depressive disorder (TR-MDD). Methods: This is a retrospective study comparing rTMS treatment outcomes between patients taking benzodiazepines (n = 59) and those who were not (n = 136). Participants completed the HAM-A, HAM-D17, MADRS and ZUNG at baseline and at the end of treatment. Results: Patients taking benzodiazepines during rTMS treatment did not show any difference in partial response, response or remission rates compared to patients not treated with benzodiazepines. There was a significant decrease (p <.0001) in depression and anxiety scores from baseline to post-treatment among both groups. Conclusions: Concomitant benzodiazepine treatment had no effect on the efficacy of rTMS treatment of TRD, contrary to previous research. [ABSTRACT FROM AUTHOR]

Introduction: Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Methods: Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Results: Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML. DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pretreatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). Discussion: These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms. [ABSTRACT FROM AUTHOR]

Obsessive compulsive disorder (OCD) represents a complex and often difficult to treat disorder. Pharmacological and psychotherapeutic interventions are often associated with sub-optimal outcomes, and 40–60% of patients are resistant to first line therapies and thus left with few treatment options. OCD is underpinned by aberrant neurocircuitry within cortical, striatal, and thalamic brain networks. Considering the neurocircuitry impairments that underlie OCD symptomology, neurostimulation therapies provide an opportunity to modulate psychopathology in a personalized manner. Also, by probing pathological neural networks, enhanced understanding of disease states can be obtained. This perspective discusses the clinical efficacy of TMS and DBS therapies, treatment access options, and considerations and challenges in managing patients. Recent scientific progress is discussed, with a focus on neurocircuitry and biopsychosocial aspects. Translational recommendations and suggestions for future research are provided. There is robust evidence to support TMS and DBS as an efficacious therapy for treatment resistant OCD patients supported by an excellent safety profile and favorable health economic data. Despite a great need for alternative therapies for chronic and severe OCD patients, resistance toward neurostimulation therapies from regulatory bodies and the psychiatric community remains. The authors contend for greater access to TMS and DBS for treatment resistant OCD patients at specialized sites with appropriate clinical resources, particularly considering adjunct and follow-up care. Also, connectome targeting has shown robust predictive ability of symptom improvements and holds potential in advancing personalized neurostimulation therapies. [ABSTRACT FROM AUTHOR]

BackgroundWhen physician assisted dying (referred to as Medical Assistance in Dying or MAiD in this article) is available for individuals with mental disorders as the sole underlying medical condition (MD-SUMC), patients with borderline personality disorder (BPD) frequently request MAiD. Psychiatrists and other clinicians must be prepared to evaluate and manage these requests.ObjectivesThe purposes of this paper are to define when patients with BPD should be considered to have an irremediable, treatment resistant disorder and provide clinicians with an approach to assess and manage their patients with BPD making requests for MAiD.MethodsThis perspective paper developed the authors’ viewpoint by using a published, authoritative definition of irremediability and including noteworthy systematic and/or meta-analytic reviews related to the assessment of irremediability.ResultsThe clinician must be aware of the eligibility requirements for granting MAiD in their jurisdiction so that they can appropriately prepare themselves and their patients for the assessment process. The appraisal of the intolerability of the specific person’s suffering comes from having an extensive dialogue with the patient; however, the assessment of whether the patient has irremediable BPD should be more objectively and reliably determined. A systematic approach to the assessment of irremediability of BPD is reviewed in the context of the disorder’s severity, treatment resistance and irreversibility.ConclusionIn addition to characterizing irremediability, this paper also addresses the evaluation and management of suicide risk for patients with BPD undergoing the MAiD assessment process.

Introduction: Subanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance. Methods: Patients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction. Results: Patients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML. DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pretreatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007). Discussion: These results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a multisystem granulomatous disease with a wide variety of presentations and clinical courses. Cutaneous manifestations and comorbidities associated with sarcoid prognosis remain understudied. Methods: An EPIC query was run for patients age 18+ at the Johns Hopkins Hospital with a diagnosis of sarcoidosis of the skin according to the ICD-10-CM code D86.3. Data were obtained from a population-based sample of 240 patients from 2015 to 2020. Results: A total of 240 patients were included in the cohort study. The mean (SD) age was 43.76 (11.72) years, and 30% of participants were male; 76.25% of patients identified as black, 19.58% as white, and 4.17% as other. The average age of onset in remissive patients was significantly higher than progressive (47 ± 12 vs. 40 ± 10, p = 0.0005); 49% of black patients experienced progressive sarcoid compared to 32.6% of white patients (p = 0.028). Progressive disease was associated with the presence of lupus pernio (aOR = 3.29, 95% CI, 1.60–6.77) and at least one autoimmune comorbidity (aOR 6.831, 95% CI 1.819–11.843). Conclusions: When controlling for patient demographics, lupus pernio and the presence of at least one autoimmune condition were associated with progressive cutaneous sarcoidosis. [ABSTRACT FROM AUTHOR]

IntroductionSubanesthetic ketamine is a rapidly acting antidepressant that has also been found to improve neurocognitive performance in adult patients with treatment resistant depression (TRD). Provisional evidence suggests that ketamine may induce change in hippocampal volume and that larger pre-treatment volumes might be related to positive clinical outcomes. Here, we examine the effects of serial ketamine treatment on hippocampal subfield volumes and relationships between pre-treatment subfield volumes and changes in depressive symptoms and neurocognitive performance.MethodsPatients with TRD (N = 66; 31M/35F; age = 39.5 ± 11.1 years) received four ketamine infusions (0.5 mg/kg) over 2 weeks. Structural MRI scans, the National Institutes of Health Toolbox (NIHT) Cognition Battery, and Hamilton Depression Rating Scale (HDRS) were collected at baseline, 24 h after the first and fourth ketamine infusion, and 5 weeks post-treatment. The same data was collected for 32 age and sex matched healthy controls (HC; 17M/15F; age = 35.03 ± 12.2 years) at one timepoint. Subfield (CA1/CA3/CA4/subiculum/molecular layer/GC-ML-DG) volumes corrected for whole hippocampal volume were compared across time, between treatment remitters/non-remitters, and patients and HCs using linear regression models. Relationships between pre-treatment subfield volumes and clinical and cognitive outcomes were also tested. All analyses included Bonferroni correction.ResultsPatients had smaller pre-treatment left CA4 (p = 0.004) and GC.ML.DG (p = 0.004) volumes compared to HC, but subfield volumes remained stable following ketamine treatment (all p > 0.05). Pre-treatment or change in hippocampal subfield volumes over time showed no variation by remission status nor correlated with depressive symptoms (p > 0.05). Pre-treatment left CA4 was negatively correlated with improved processing speed after single (p = 0.0003) and serial ketamine infusion (p = 0.005). Left GC.ML.DG also negatively correlated with improved processing speed after single infusion (p = 0.001). Right pre-treatment CA3 positively correlated with changes in list sorting working memory at follow-up (p = 0.0007).DiscussionThese results provide new evidence to suggest that hippocampal subfield volumes at baseline may present a biomarker for neurocognitive improvement following ketamine treatment in TRD. In contrast, pre-treatment subfield volumes and changes in subfield volumes showed negligible relationships with ketamine-related improvements in depressive symptoms.

Purpose of Review: The following review will explore ketamine's antidepressant and antisuicidal properties in adults, review of what is known about ketamine's safety in children, and summarize the limited information we have on ketamine's role in treating depression and suicidal ideation in adolescents with depression. Future directions for ketamine's role in child psychiatry based on animal and adult studies will also be explored. Recent Findings: Over the past 20 years, ketamine has emerged as a novel treatment for depression and suicidal ideation in adults. In recent years, these studies have been extended to adolescents. In 2021, the first placebo-controlled trial examining ketamine's antidepressant potential in adolescents was performed, demonstrating superior efficacy over midazolam. Summary: Initial studies suggest that ketamine functions as a rapidly acting antidepressant in adolescents. Case reports suggest that ketamine may also reduce suicidal ideation in this population. However, existing studies are small, and more research is needed to solidify these findings and inform clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Biliary tract cancer is rare in the US but remains a highly lethal cancer. While the standard of care in the first-line, metastatic setting is well-established, no second-line regimen has been clearly defined as the gold standard. Many novel biomarker-targeted therapies have emerged and shown promise, even in treatment-refractory patients. Here, we seek to provide updates on the landscape of targeted therapies available for the treatment of advanced biliary tract cancer. Targeted therapies in biliary tract cancer (BTC) are emerging as options for patients not who do not respond to first-line treatment. Agents acting on tumor-specific oncogenes in BTC may target fibroblast growth factor receptor 2 (FGFR2), isocitrate dehydrogenase (IDH), B-raf kinase (BRAF), and human epidermal growth factor receptor 2 (HER-2). Additionally, given the heterogeneous genetic landscape of advanced BTCs, many harbor genetic aberrations that are common among solid tumors, including RET fusions, tropomyosin receptor kinase (TRK) fusions, and high tumor mutational burden (TMB). This review aims to provide updates on the evolving array of therapeutics available, and to summarize promising works on the horizon. [ABSTRACT FROM AUTHOR]

Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants' mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted. [ABSTRACT FROM AUTHOR]

IntroductionEarly intervention may significantly improve the prognosis associated with psychotic disorders in adulthood.MethodsThe present study examined the acceptability and effectiveness of a standalone intensive, in-home, mentalization-based treatment (MBT) for extremely high-risk, non-help-seeking youth on the psychotic spectrum [Equipo Clínico de Intervención a Domicilio (ECID), Home Intervention Clinical Team].ResultsDespite previously being unable to participate in treatment, more than 90% of youth engaged and those on the psychotic spectrum demonstrated slightly higher engagement than the general high-risk group (95% and 85%, respectively, X1 = 4.218, p = 0.049). Generalized estimating equation (GEE) models revealed no main group effect on the likelihood of reengaging with school over the first 12 months of treatment (X1 = 1.015, p = 0.314) when controlling for the duration of school absenteeism at intake. Overall, the percentage of school engagement rose from 12 to 55 over this period, more than 40% of the total sample experienced clinically reliable change and an additional 50% appeared clinically stable. No statistically significant difference was observed between the groups in the average change in HoNOSCA total severity score (X1 = 0.249, p = 0.618) or the distribution of youth into categories of clinical change during the first year of treatment (X1 = 0.068, p = 0.795).DiscussionThe present findings suggest that a mentalization based intervention may be able to engage extremely high-risk youth in treatment and have clinically meaningful impact on symptom severity and functioning after 12 months.

Nocturnal enuresis is defined as intermittent urinary incontinence during sleep in children 5 years of age and older, occurring at least once a month for at least 3 months. In Japan, pediatricians who do not specialize in nocturnal enuresis have become more proactive in treating the condition since 2016, when the guidelines for treating it were revised for the first time in 12 years. For monosymptomatic nocturnal enuresis, the first step is lifestyle guidance, with a focus on the restriction of fluid intake at night; however, if lifestyle guidance does not decrease the frequency of nocturnal enuresis, aggressive treatment should be added. The first choice of aggressive treatment is oral desmopressin, an antidiuretic hormone preparation, or alarm therapy. However, there remain patients whose wet nights do not decrease with oral desmopressin or alarm therapy. In such cases, it is necessary to reconfirm the method of desmopressin administration and check for factors that may decrease the efficacy of desmopressin. If alarm therapy does not increase the number of dry nights, it is possible that the patient is fundamentally unsuitable for alarm therapy. If dry nights do not increase with oral desmopressin or alarm therapy, the next treatment strategy should be considered immediately to keep the patient motivated for treatment. [ABSTRACT FROM AUTHOR]

Background: Sarcoidosis is a multisystem granulomatous disease with a wide variety of presentations and clinical courses. Cutaneous manifestations and comorbidities associated with sarcoid prognosis remain understudied. Methods: An EPIC query was run for patients age 18+ at the Johns Hopkins Hospital with a diagnosis of sarcoidosis of the skin according to the ICD-10-CM code D86.3. Data were obtained from a population-based sample of 240 patients from 2015 to 2020. Results: A total of 240 patients were included in the cohort study. The mean (SD) age was 43.76 (11.72) years, and 30% of participants were male; 76.25% of patients identified as black, 19.58% as white, and 4.17% as other. The average age of onset in remissive patients was significantly higher than progressive (47 ± 12 vs. 40 ± 10, p = 0.0005); 49% of black patients experienced progressive sarcoid compared to 32.6% of white patients (p = 0.028). Progressive disease was associated with the presence of lupus pernio (aOR = 3.29, 95% CI, 1.60–6.77) and at least one autoimmune comorbidity (aOR 6.831, 95% CI 1.819–11.843). Conclusions: When controlling for patient demographics, lupus pernio and the presence of at least one autoimmune condition were associated with progressive cutaneous sarcoidosis.

Introduction: To compare the safety and efficacy of antivascular endothelial growth factor (anti-VEGF) monotherapy vs anti-VEGF and steroid combination therapy in treatment-naïve and treatment-resistant patients with diabetic macular edema (DME). Methods : A systematic literature search was conducted from January 2005 to December 2022. Sixteen randomized control trials (RCTs) published in English that reported the efficacy or safety of monotherapy and combination therapy in patients with DME were included. Results: The 16 RCTs included 1166 eyes. Monotherapy was associated with a significantly better best-corrected visual acuity (BCVA) at the final follow-up (weighted mean difference [WMD], -0.04 logMAR; 95% CI, -0.07 to -0.02; P  = .002; I 2  = 0%). No significant differences were observed in the change in BCVA between groups at the final observation. Monotherapy was associated with a significantly smaller change in retinal thickness at the final follow-up (WMD, 37.63 μm; 95% CI, 11.67-63.60; P  = .005; I 2  = 78%) and with a significantly lower risk for intraocular pressure-related adverse events (AEs) (risk ratio, 0.27; 95% CI, 0.15-0.46; P  ≤ .001; I 2  = 0%). The risk for cataract-related AEs was not significantly different between groups ( P  = .06). The results in treatment-naïve patients were similar. In treatment-resistant patients, the change in retinal thickness at the final follow-up was similar between groups ( P  = .14) but the risk for cataract-related AEs was significantly lower in the monotherapy group in 2 RCTs (risk ratio, 0.09; 95% CI, 0.01-0.66; P  = .02; I 2  = 0%). Conclusions: The changes in BCVA were similar despite combination therapy being associated with greater changes in retinal thickness. However, increased complications were seen with combination therapy. Most results in treatment-naïve patients and treatment-resistant patients were similar., Competing Interests: Dr. Choudhry is a consultant to Topcon, Optos, Bayer, Allergan, Novartis, Carl Zeiss Meditec, and Ellex and receives research equipment from Topcon, Optos, and Carl Zeiss Meditec. None of the other authors declared potential conflicts of interest., (© The Author(s) 2024.)

Background: There are conflicting reports on the association between children with increased body mass index (BMI), and constipation. This retrospective chart review of two groups of children from a primary care clinic was designed to address the controversy.Methods: Group-1: Charts of all children seen in a year for general pediatric care were reviewed for incidences of increased BMI (>85th percentile) and constipation as well as overweight recognition in the final diagnosis; Group-2: Children diagnosed with constipation at the same primary care setting for 5 years were identified by ICD-9 code. These charts were reviewed for prevalence of increased BMI and incidences of referral to subspecialty clinic.Results: Group-1: Three hundred nineteen (33.4%) of the 955 children had increased BMI and 28 (2.93%) had constipation. The prevalence of constipation was not increased among children with increased BMI. Group-2: 24 of the 66 children with constipation were referred to the pediatric gastroenterology clinic. children with increased BMI were three times more likely to be referred (n = 20, p = 0.04). The two groups had a similar prevalence of children with increased BMI (Group 1 = 33.4%; Group 2 = 30.3%).Conclusion: In the general pediatric population, children with an increased BMI were not at an increased risk of developing constipation. However, children with increased BMI and constipation were three times more likely to be referred, presumably for treatment failure, to the pediatric gastroenterology clinic .Hence children with increased BMI were more likely to develop treatment resistant constipation. [ABSTRACT FROM AUTHOR]

Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants’ mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.

Objective: To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents.Methods: We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model.Results: A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB.Limitations: Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons.Conclusions: This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD. [ABSTRACT FROM AUTHOR]

Andreea Teodorescu,1 Petru Ifteni,1 Ana Dragan,2 Marius Alexandru Moga,1 Ana Aliana Miron,1 Lorena Dima1 1Transilvania University of Brasov, Faculty of Medicine, Brasov, Romania; 2Clinical Hospital of Psychiatry and Neurology of Brasov, 3rd Department of Clinical Psychiatry, Brasov, RomaniaCorrespondence: Petru IfteniTransilvania University of Brasov, Faculty of Medicine, 29th Eroilor Bvd, Brasov, RomaniaTel +40724993329Email petru_ifteni@yahoo.comBackground: The postpartum period is a difficult time for mother and family. Unfortunately, in some cases, two psychiatric complications may occur: postpartum psychoses (PPP) with a prevalence of 0.2% and a very low incidence of 0.25– 0.50 per 1000 deliveries, and post-natal depressions with an incidence of 10 to 20% per 1000 deliveries. The onset of postpartum psychosis is in the first 4 weeks after childbirth with symptoms such as emotional lability, cognitive disorganization, delusional beliefs and hallucinations. It requires hospitalization due to the high risk of suicide and infanticide. The studies reveal that the treatment can include FGAs (first-generation antipsychotics), such as haloperidol, and SGAs (second-generation antipsychotics), such as olanzapine, quetiapine and risperidone. The literature is scarce in what resistant PPP is concerned and no such cases treated with clozapine have been reported, according to our knowledge. The present case report focuses on a female diagnosed with PPP who was treated with clozapine due to the lack of response to adequate dosage of 2 second-generation antipsychotics.Case Presentation: We present the case of a 30-year-old primiparous woman on her 3rd day after delivery, admitted in the psychiatric emergency unit for agitation, intrusive thoughts with a content frequently related to the infant, ideas of reference, disorganized speech, bizarre behavior, verbal stereotypes, insomnia and anxiety. Due to lack of response to adequate dosage of 2 second-generation antipsychotics, clozapine was initiated up to 250 mg/day. The symptoms remitted in the next 5 days and the patient was discharged. After discharge, at the patient’s request, clozapine was replaced by olanzapine. Visit at 1 year revealed full remission of symptoms.Conclusion: Although data is extremely limited, clozapine has been shown to be effective and safe in a severe case of treatment-resistant PPP.Keywords: postpartum psychosis, antipsychotics, clozapine, suicide, treatment-resistant

Introduction Electroconvulsive therapy (ECT) is one of the oldest psychiatric treatments used to this day. It is particularly useful in cases of schizophrenia resistant to treatment with antipsychotics. 49% of patients with schizophrenia experience little or no response with one trial of antipsychotics, 71% do not achieve remission and up to 20% of patients are also resistant to clozapine. Objectives Description of a clinical case where ECT is used in the treatment of resistant schizophrenia and review of the literature. Methods Description of a clinical case. Non systematic review of the literature, searching the terms “treatment resistant”; “schizophrenia”; “ect” in the databases Pubmed, Medline, Cochrane and Uptodate. Results Male, 38-year-old patient, diagnosed with schizophrenia for 20 years, with history of multiple hospitalizations, institutionalized for 9 years. Treated with risperidone 50 mg intramuscular fortnightly, clozapine 750 mg daily, aripiprazol 30 mg daily and diazepam 10 mg daily. He presented with increased delusional intensity for a year. Hospitalized for treatment with ECT, submitted to 12 sessions with bitemporal stimuli, with effective convulsions. MoCA, PANSS and BPRS were applied before and after treatment, with an increase of 25% in MoCA and a decrease of 47.3% and 57.9% respectively, in the psychotic symptoms scales. Conclusions We present a case of schizophrenia resistant to treatment with multiple antipsychotics, including clozapine. ECT was used, with clinically demonstrated efficacy. In the future, it might be interesting to study in detail the mechanism of action of this treatment with the goal of deepening the knowledge of the neurobiology of schizophrenia. Disclosure No significant relationships.

Introduction Despite the efficacy of antipsychotics, up to about 30% of schizophrenia patients do not respond adequately to treatment and are called treatment-resistant schizophrenia (TRS) patients. The treatment of choice in these patients is clozapine, which is used last due to the adverse effects it can cause. However, it has been shown that half of TRSs are also resistant to clozapine, leading to ultra-resistant schizophrenia. Objectives We present a clinical case corresponding to a 33-year-old man, single, residing in a community residence, undergoing psychiatric follow-up from the age of 7, receiving during this period the diagnoses of schizotypal personality disorder and paranoid schizophrenia. Methods As of 2015, he began to make autolytic attempts, the last being this year, 2021. Moment in which he manifests for the first time presenting imperative, sporadic auditory pseudo-hallucinations, which incite self-harm. These sensory-perceptual alterations appeared from 2015, together with the worsening of the negative symptoms. Results The patient has been treated with numerous antipsychotics, without complete remission, so since 2019 treatment with Clozapine 200mg was started. As the symptoms did not subside, the dose was increased to 400mg, at which point some of its side effects began to appear; urinary incontinence, sedation, sexual impotence … so the patient abandoned the treatment, suffering a relapse of his mental pathology. Conclusions Despite the arrival of atypical antipsychotics, it remains a challenge that there is a complete remission of symptoms in some patients with schizophrenia, for which we consider that psychopharmacological research in this group of patients is of the utmost importance. Disclosure No significant relationships.

Background: To study the efficacy of repetitive Transcranial Magnetic Stimulation (rTMS) in Major Depressive Disorder (MDD) including comorbidities of Generalized Anxiety Disorder (GAD), Post-Traumatic Stress Disorder (PTSD), and Borderline Personality Disorder (BPD). We compared response and remission rates to a single question patient-reported outcome (PRO). Methods: A retrospective review of patients completing rTMS from 1/2009-2/2021. Standard response (≥50% reduction in Patient Health Questionnaire-9 [PHQ-9]) and remission (PHQ-9 ​

Background: Pain strongly coexists with depression. Ketamine has great analgesic and antidepressant effects, acting as a promising role in treating depression with pain. Few studies have evaluated impact of pain symptoms on antidepressant effect of ketamine infusions. Thus, present study investigated whether pain symptoms in individuals with depression moderate response to ketamine. Methods: One hundred and four individuals with major depressive disorder and bipolar depression received six intravenous infusions of ketamine. The Montgomery–Åsberg Depression Rating Scale (MADRS) was administered at baseline, the next morning after each infusion and 2 weeks (Day 26) after the last infusion. Pain symptoms were collected at baseline using the short-form McGill Pain Questionnaire (SF-MPQ). Results: The prevalence of pain in patients with depression was 48.8%. Mix model analyses showed that pre-treatment pain symptoms assessed by each domain of SF-MPQ significantly moderated antidepressant response to six infusions of ketamine from baseline to day 26 (all p < 0.05). Then follow-up simple slopes analyses suggested that all patients across groups showed a significant symptomatic improvement after ketamine infusions (all p < 0.05), and patients with severe pain (across all domains of SF-MPQ) had greater improvement in depressive symptoms than those with mild pain or non-pain (all p < 0.05). Conclusion: A significant and rapid improvement in depressive symptoms was observed in patients with depression and pain after ketamine treatment. Ketamine may be a novel and promising antidepressant preferentially for the therapy of depression with severe pain. [ABSTRACT FROM AUTHOR]

Abstract Introduction Depression is one of the most important psychiatric disorders, and the rate of recurrence is high. The heavy cost burden of depression is probably due to treatment-resistant depression. The purpose of this study was to determine the effectiveness of mindfulness-based cognitive therapy (MBCT) in patients with treatment-resistant depression (TRD). Method The present study was a quasi-experimental study conducted with twenty-four patients with treatment-resistant depression. Participants were selected by purposive sampling and randomly assigned to two groups, an experimental group and a control group. The experimental group received MBCT and antidepressants, while the control group received antidepressants only. The Hamilton and Beck Depression Inventory, Self-Compassion Scale, Thought Rumination Scale, and Mindfulness Scale were administered. The treatment program was conducted in eight sessions; with a follow-up period of one month subsequent to treatment termination. Data were analyzed using descriptive statistics (mean and standard deviation) and inferential statistics (analysis of variance for repeated measures and Bonferroni’s post-hoc test). Results The results showed that MBCT significantly reduced depression and ruminative thinking in the experimental group and also improved mediators such as mindfulness and self-compassion. Patients maintained gains over the one month follow-up period (p < 0.01). Conclusion The present study provides additional evidence for the effectiveness of MBCT for TRD.

BackgroundPain strongly coexists with depression. Ketamine has great analgesic and antidepressant effects, acting as a promising role in treating depression with pain. Few studies have evaluated impact of pain symptoms on antidepressant effect of ketamine infusions. Thus, present study investigated whether pain symptoms in individuals with depression moderate response to ketamine.MethodsOne hundred and four individuals with major depressive disorder and bipolar depression received six intravenous infusions of ketamine. The Montgomery–Åsberg Depression Rating Scale (MADRS) was administered at baseline, the next morning after each infusion and 2 weeks (Day 26) after the last infusion. Pain symptoms were collected at baseline using the short-form McGill Pain Questionnaire (SF-MPQ).ResultsThe prevalence of pain in patients with depression was 48.8%. Mix model analyses showed that pre-treatment pain symptoms assessed by each domain of SF-MPQ significantly moderated antidepressant response to six infusions of ketamine from baseline to day 26 (all p < 0.05). Then follow-up simple slopes analyses suggested that all patients across groups showed a significant symptomatic improvement after ketamine infusions (all p < 0.05), and patients with severe pain (across all domains of SF-MPQ) had greater improvement in depressive symptoms than those with mild pain or non-pain (all p < 0.05).ConclusionA significant and rapid improvement in depressive symptoms was observed in patients with depression and pain after ketamine treatment. Ketamine may be a novel and promising antidepressant preferentially for the therapy of depression with severe pain.

Introduction: Treatment resistant schizophrenia (TRS), affecting approximately one-third of patients with schizophrenia, is associated with a serious impairment in global psychosocial functioning. Clozapine is the only licensed drug for TRS. However its prescription remains limited by its side effects requiring mandatory monitoring. The need to identify clinical factors associated with good response to clozapine in TRS has been established. The presence of ethnic differences in these factors and the scarcity of data on the Tunisian or more generally the North-African population warrants the conduct of a clinical study on the subject. The aim of this study was to investigate demographic, clinical, and biochemical patient characteristics as potential predictors of response to clozapine. Methods: This is a cross-sectional and retrospective study, at the “F and A psychiatry departments” of Razi Hospital in Manouba, Tunisia. All patients, with DSM 5 diagnosis of schizophrenia in its resistant form, on clozapine for at least 12 months and who consulted from June 1, 2018 to November 30, 2018 were included. We investigated premorbid functioning by the premorbid adjusment scale, demographic and clinical characteristics, and clozapine plasma level as potential clozapine response predictors. The response to clozapine was defined by a total BPRS score of 35 or less. Results: Sixty-three patients were included in the study. The mean age at clozapine introduction was 30,84 ±9,25 years. The mean duration of clozapine treatment was 7,22 ± 4,02 years.There were 16 clozapine responders (25%) who had BPRS total scores below or equal to 35 and 47 non-responders (75%).A higher premorbid social functioning in childhood (p = 0,018) and early adolescence (p = 0,024) was associated with better response to clozapine. A delay clozapine initiation shorter than 7 years(p = 0,036), one atypical antipsychotic trial (p = 0,029) and schizophrenia paranoid subtype (p

Non-Invasive Brain Stimulation (NIBS) techniques and in particular, repetitive Transcranial Magnetic Stimulation (rTMS), are developing beyond mere clinical application. Although originally purposed for the treatment of resistant neuropsychiatric disorders, NIBS is also contributing to a deeper understanding of psychiatric disorders. rTMS is also changing the model of the disorder itself, from "mental" to one of neural connectivity. TMS allows the assessment of brain circuit excitability and eventually, of plastic changes affecting these circuits. While a clinical translational approach is, at the present time, the most adequate to meet the dimensional-circuit base model of the disorder, it refines the standard categorical classification of psychiatric disorders. The discovery of the fundamental importance of the balance between neuroplasticity and inflammation is also now explored through neuro-modulation findings consistently with the evidence of anti-inflammatory actions of the magnetic pulses. rTMS may activate, inhibit, or otherwise interfere with the activity of neuronal cortical networks, depending on stimulus frequency and intensity of brain-induced electric field. Of particular interest, yet still unclear, is how the relatively unspecific nature of TMS stimulation may lead to specific neuronal reorganization, as well as a definition of the TMS-triggered reorganization of functional brain modules, raising attention on the importance of the active participation of the patient to the treatment.. Configuration and state of consciousness of the subject have made subjective experience under treatment regain importance in the neuro-scientific Psychiatry based on the requirement of United States National Institute of Health (NIH) and the substantial importance of the consciousness state in the efficacy of the TMS treatment. By focusing on the subjective experience, a renaissance of the phenomenology offers Psychiatry an opportunity to become proficient and to distinguish itself from other disciplines. For all these reasons, TMS should be included in the cluster of the sub-specialties as a new "Super-Specialty" and an appropriate training course has to be inaugurated. Psychiatrists are nowadays multi-specialists, moving from a specialty to another, vs super-specialist. The cultivation of a properly trained cohort of TMS psychiatrists will better meet the challenges of treatment-resistant psychiatric conditions (disorders of connectivity), through appropriate and ethical practice, meanwhile facilitating an informed development and integration of additional emerging neuro-modulation techniques. The aim of this consensus paper is to underline the interdisciplinary nature of NIBS, that also encompasses the subjective experience and to point out the necessity of a neuroscience-applied approach to NIBS in the context of the European College of Neuro-psychopharmacology (ECNP). [ABSTRACT FROM AUTHOR]

Summary: Objective: Lennox–Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add‐on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long‐term open‐label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5. Methods: Patients received plant‐derived highly purified CBD (Epidiolex in the United States; Epidyolex in the European Union; 100 mg/ml oral solution), titrated to a target maintenance dose of 20 mg/kg/day over 2 weeks. Based on response and tolerability, CBD could then be reduced or increased up to 30 mg/kg/day. Results: Of 368 patients with LGS who completed the RCTs, 366 (99.5%) enrolled in this OLE. Median and mean treatment duration were 1090 and 826 days (range = 3–1421), respectively, with a mean modal dose of 24 mg/kg/day. Adverse events (AEs) occurred in 96% of patients, serious AEs in 42%, and AE‐related discontinuations in 12%. Common AEs were convulsion (39%), diarrhea (38%), pyrexia (34%), and somnolence (29%). Fifty‐five (15%) patients experienced liver transaminase elevations more than three times the upper limit of normal; 40 (73%) were taking concomitant valproic acid. Median percent reductions from baseline ranged 48%–71% for drop seizures and 48%–68% for total seizures through 156 weeks. Across all 12‐week visit windows, 87% or more of patients/caregivers reported improvement in the patient's overall condition on the Subject/Caregiver Global Impression of Change scale. Significance: Long‐term add‐on CBD treatment had a similar safety profile as in the original RCTs. Sustained reductions in drop and total seizure frequency were observed for up to 156 weeks, demonstrating long‐term benefits of CBD treatment for patients with LGS. [ABSTRACT FROM AUTHOR]

• The left corpus callosum (CC) was statistically significantly thicker in the TRS patient group as compared to the non-TRS group. • Significant difference was not determined in the other brain regions. • Correlation analyses revealed positive correlation between the left CC thickness and PANSS scores, disease duration and age at disease onset in overall schizophrenia patients. • It was found to be left CC thickness positively correlated only with PANSS scores in the TRS patient group. Recent developments in neuroimaging have improved our understanding of the biological mechanisms underlying schizophrenia. However, neuroimaging findings in treatment-resistant schizophrenia (TRS) remain unclear. In the present study, we aimed to explore potential neuroanatomical regions that may be associated with treatment resistance in schizophrenia patients by comparing neuroanatomical regions of TRS and non-TRS patients using the MRICloud method. A total of 33 schizophrenia patients (meeting DSM 5 diagnostic criteria for schizophrenia) were included in the study. Patients were dichotomized into TRS (n = 18) and non-TRS (n = 15) groups, and all patients underwent MRI. Neuroanatomical regions of TRS and non-TRS patients were compared using the MRICloud method. Disease severity was measured using the Positive and Negative Syndrome Scale (PANSS). Interestingly, a statistically significant greater left Corpus Collosum (CC) thickness was found in TRS patients compared to non-TRS patients. It is clear that further studies comparing TRS patients with non-TRS patients are needed, and these studies should focus on the circuits in the corpus callosum that are thought to play a role in treatment resistance. Further longitudinal studies are also needed to complement the cross-sectional studies, using a multimodal imaging approach in the patients with clearly defined TRS criteria. [ABSTRACT FROM AUTHOR]

Abstract Background The treatment of homeless dual-diagnosis patients (i.e., those with severe mental illness and substance-use disorder) is difficult and often fails. For patients in the Netherlands who had not responded to earlier voluntary and compulsory treatment, a new treatment facility – Sustainable Residence (SuRe) – was developed to offer long-term compulsory in-patient treatment. Aim of the study To study patterns of changes in clinical and functional outcomes during treatment at SuRe and how these relate to eventual treatment outcome. Methods On the basis of the intensity of care needed after four years, three groups of patients were distinguished (total n = 165): those discharged to a less restrictive and less supportive setting (n = 70, 42%), those still hospitalized at SuRe at the end of the four-year study period (n = 69, 42%) and those referred to a more appropriate setting (n = 26, 16%). Random coefficient analysis was used to examine differences between groups regarding changes in clinical and functional outcomes during treatment. During treatment, outcomes were monitored using Routine Outcome Assessment. Results All three groups made small but significant improvements on global psychosocial functioning, distress and therapeutic alliance (effect sizes (ES) 0.11 to 0.16 per year). Patients who were discharged to a less restrictive setting showed small to moderate improvement in risk to self and others, psychiatric symptoms, and skills for daily living (ES 0.19–0.33 per year and 0.42–0.73 for their mean 2.2-year treatment period). Patients remaining at SuRe showed a small increase in risk to self (ES 0.20 per year; 0.80 for their treatment period of four years or more). Oppositional behaviour was consistently greater in referred patients than in the other groups (ES 0.74–0.75). Conclusion Long-term compulsory treatment appeared to have helped improve clinical and functional outcomes in a substantial proportion (42%) of previously severely dysfunctional, treatment-resistant dual-diagnosis patients, who could then be discharged to a less restrictive and less supportive environment. However, risk-to-self increased in a similar proportion. A smaller number of patients (16%) showed marked oppositional behaviour and needed a higher level of care and protection in another facility.

Abstract Background Anxiety and depressive disorders are common mental disorders. A substantial part of patients does not achieve symptomatic remission after treatment in specialized services. Current care as usual (CAU) for these patients consists of long-term supportive contacts. Termination of CAU is often not considered to be an option due to persistent symptoms, a low level of functioning, and the absence of further treatment options. A new intervention, ZemCAD, offers a program focused on rehabilitation and self-management, followed by referral back to primary care. Methods This multicenter randomized controlled trial was carried out in twelve specialized outpatient mental health care services in the Netherlands. Consenting and eligible patients were invited for the MINI interview and the baseline questionnaire. Assessments were done at 6 (T1), 12 (T2) and 18 (T3) months post baseline. We used linear mixed model analysis (LMM) to ascertain the effectiveness of the ZemCAD group relative to the CAU group on quality of life, symptom severity and empowerment. Results In total 141 patients were included. The results at 18-month follow-up regarding to quality of life and symptom severity, showed no significant differences between the ZemCAD group and the CAU group, except on the ‘social relationships’-domain (d = 0.37). With regard to empowerment a significant difference between both groups was observed in the total empowerment score and one empowerment dimension (d = 0.45 and d = 0.39, respectively). After the ZemCAD intervention, more patients went from specialized outpatient mental health services back to a less specialized health care setting with less intensive treatment, such as primary care. Conclusion The findings in this study suggest that patients with chronic and treatment-resistant anxiety and depression using the ZemCAD intervention improve on empowerment but not on symptom severity or quality of life. Since little is known about the effects of rehabilitation and self-management in patients with chronic and treatment resistant anxiety and depressive disorders, this is a first attempt to provide a proof-of-concept study in this under-researched but important field. Trial registration Netherlands Trial Register: NTR3335, registered 7 March 2012.

Background: Treatment-resistant depression (TRD) is a debilitating chronic mental illness that confers increased morbidity and mortality, decreases the quality of life, impairs occupational, social, and offspring development, and translates into increased costs on the healthcare system. The goal of this study is to reach an agreement on the concept, definition, staging model, and assessment of TRD. Methods: This study involved a review of the literature and a modified Delphi process for consensus agreement. The Appraisal of Guidelines for Research & Evaluation II guidelines were followed for the literature appraisal. Literature was assessed for quality and strength of evidence using the grading, assessment, development, and evaluations system. Canadian national experts in depression were invited for the modified Delphi process based on their prior clinical and research expertize. Survey items were considered to have reached a consensus if 80% or more of the experts supported the statement. Results: Fourteen Canadian experts were recruited for three rounds of surveys to reach a consensus on a total of 27 items. Experts agreed that a dimensional definition for treatment resistance was a useful concept to describe the heterogeneity of this illness. The use of staging models and clinical scales was recommended in evaluating depression. Risk factors and comorbidities were identified as potential predictors for treatment resistance. Conclusions: TRD is a meaningful concept both for clinical practice and research. An operational definition for TRD will allow for opportunities to improve the validity of predictors and therapeutic options for these patients. [ABSTRACT FROM AUTHOR]

Background: To assess whether linear effects or threshold effects best describe the association between early adverse stress (EAS) and complex and severe depression (i.e., depression with treatment resistance, psychotic symptoms, and/or suicidal ideation), and to examine the attributable risk of complex and severe depression associated with EAS. Methods: A cross-sectional study was conducted using deidentified clinical data (on demographics, presence of complex and severe depression, and exposure to seven types of EAS) from 1,013 adults who were seen in an outpatient mental health clinic in Santiago, Chile, for a major depressive episode. Multivariate logistic regressions were fitted to estimate odds ratios (ORs), using a bootstrap approach to compute 95% bias-corrected confidence intervals (95% BC CIs). A detailed examination of the cumulative risk score and calculations of the attributable risk was conducted. Results: Exposure to at least five EASs was reported by 3.6% of the sample. In the multivariate logistic regression models, there was a marked increase in the odds of having complex and severe depression associated with exposure to at least five EASs (OR = 4.24; 95% BC CI: 1.25 to 9.09), according to a threshold effect. The attributable risk of complex and severe depression associated with exposure to at least one EAS was 36.8% (95% BC CI: 17.7 to 55.9). Conclusions: High levels of EAS distinctively contribute to complex clinical presentations of depression in adulthood. Patients with complex clinical presentations of depression and history of EAS should need a differentiated treatment approach, particularly those having high levels of EAS. [ABSTRACT FROM AUTHOR]

Objective: Antipsychotic compounds are known to induce sedation somnolence and have expanded clinical indications beyond schizophrenia to regulatory approval in bipolar disorder, treatment-resistant depression, and is being repurposed in infectious diseases and oncology. However, the medical sciences literature lacks a comprehensive association between sedation and somnolence among a wide-range of antipsychotic compounds. The objective of this study is to assess the disproportionality of sedation and somnolence among thirty-seven typical and atypical antipsychotics.Materials and Methods: Patient adverse drug reactions (ADR) cases were obtained from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) between January 01, 2004 and September 30, 2020 for a wide-array of clinical indications and off-label use of antipsychotics. An assessment of disproportionality were based on cases of sedation and somnolence and calculated using the case/non-case methodology. Statistical analysis resulting in the reporting odds-ratio (ROR) with corresponding 95% confidence intervals (95% CI) were conducted using the R statistical programming language.Results: Throughout the reporting period, there were a total of 9,373,236 cases with 99,251 specific ADRs reporting sedation and somnolence. Zuclopenthixol (n = 224) ROR = 13.3 (95% CI, 11.6–15.3) was most strongly associated of sedation and somnolence and haloperidol decanoate long-acting injection (LAI) was not statistically associated sedation and somnolence. Further, among atypical antipsychotic compounds, tiapride and asenapine were the top two compounds most strongly associated with sedation and somnolence. Comprehensively, the typical antipsychotics ROR = 5.05 (95%CI, 4.97–5.12) had a stronger association with sedation and somnolence when compared to atypical antipsychotics ROR = 4.65 (95%CI, 4.47–4.84).Conclusion: We conducted a head-to-head comparison of thirty-seven antipsychotics and ranked the compounds based on the association of sedation and somnolence from ADR data collected throughout 16 years from the FAERS. The results are informative and with recent interests in repurposing phenothiazine antipsychotics in infectious disease and oncology provides an informative assessment of the compounds during repurposing and in psychopharmacology.

Introduction: Psychological support throughout psilocybin therapy is mandated by regulators as an essential part of ensuring participants' physical and psychological safety. There is an increased need for specially trained therapists who can provide high-quality care to participants in clinical studies. This paper describes the development and practical implementation of a therapist training program of psychological support within a current phase IIb international, multicenter, randomized controlled study of psilocybin therapy for people experiencing treatment-resistant depression.Description of Training Program: This new and manualized approach, based on current evidence-based psychotherapeutic approaches, was developed in partnership with different mental health researchers, practitioners, and experts; and has been approved by the FDA. Training consists of four components: an online learning platform; in-person training; applied clinical training; and ongoing individual mentoring and participation in webinars.This paper provides a brief overview of the method of support, the rationale and methodology of the training program, and describes each stage of training. The design and implementation of fidelity procedures are also outlined.Lessons Learned: As part of the phase IIb study of psilocybin therapy for treatment-resistant depression, 65 health care professionals have been fully trained as therapists and assisting therapists, across the US, Canada and Europe. Therapists provided informal feedback on the training program. Feedback indicates that the didactic and experiential interactive learning, delivered through a combination of online and in-person teaching, helped therapists build conceptual understanding and skill development in the therapeutic approach. Clinical training and engagement in participant care, under the guidance of experienced therapists, were considered the most beneficial and challenging aspects of the training.Conclusions: Clinical training for therapists is essential for ensuring consistently high-quality psilocybin therapy. Development of a rigorous, effective and scalable training methodology has been possible through a process of early, active and ongoing collaborations between mental health experts. To maximize impact and meet phase III and post-approval need, enhanced online learning and establishing pathways for clinical training are identified as critical points for quality assurance. This will require close public, academic and industry collaboration.

Background: The issue of treatment resistance in eating disorder care is controversial. Prior research has identified multiple failed treatment attempts as a common criterion for severe and enduring anorexia nervosa, but little is known about patients who have multiple failed treatment attempts. This study was designed to compare the clinical and demographic characteristics of eating disorder patients with multiple, incomplete inpatient admissions to those with good outcomes. Understanding if these patient populations differ at initial admissions has implications for the prediction and characterization of inpatient eating disorder treatment resistance.Methods: This study analyzed existing data from a specialist inpatient eating disorder program at a large Canadian teaching hospital collected between 2000 and 2016. Treatment resistance was defined as two or more incomplete admissions and no complete admissions in the study period. Data were available on 37 patients who met this criteria, and 38 patients who had completed their first admission and remained well (defined as a BMI > 18.5 with no binging or purging behavior) 1 year after discharge. Variables of interest included age, weight, diagnoses, duration of illness, eating disorder psychopathology, eating disorder behavioral frequencies and depressive symptoms at the time of index inpatient admissions. Statistical analyses consisted of Mann–Whitney U tests, Chi-square tests, and a logistic regression.Results: In our main bivariate analyses, patients with multiple incomplete admissions were characterized by more severe eating disorder psychopathology and depressive symptoms at admission as well as an increased prevalence of the binge purge subtype of anorexia nervosa. In our exploratory multivariate analyses controlling for diagnostic subtype and depressive symptoms, severity of eating disorder psychopathology did not remain significant. No statistically significant difference in body mass index (BMI) or frequencies of eating disorder behaviors were found. A trend toward a longer duration of illness did not meet statistical significance.Conclusions: This study found that patients considered resistant to inpatient eating disorder treatment differ from those with good outcomes at initial admission. These results suggest that while treatment-resistant anorexia nervosa may be related to severe and enduring anorexia nervosa, it may also be a different concept that warrants additional research.

Objective: Clozapine is considered to be a gold standard antipsychotic in treatment resistant schizophrenia. This study aims to investigate clozapine augmentation methods utilized in schizophrenia and compare the sociodemographic characteristics, clinical features and remission states of patients whose treatments are augmented and not. Method: This study included 122 outpatients diagnosed with DSM-IV schizophrenia. Patients were assessed with the Structured Clinical Interview for DSM-IV Axis I Disorders, Positive and Negative Syndrome Scale, Clinical Global Impression Scale, Global Assessment of Functioning, Calgary Depression Scale for Schizophrenia, Panic Agoraphobia Scale, Yale-Brown Obsessive Compulsive Scale and the World Health Organization Disability Assessment Schedule II. The remission state of the patients was assessed utilizing the Remission in Schizophrenia Working Group criteria for schizophrenia. Results: Combined antipsychotic drug use was the most prevalent method utilized for clozapine augmentation. Patients on augmentation treatment were on higher daily clozapine doses and their remission rates were lower. In addition, the severity of psychopathology related with schizophrenia and comorbid symptoms, the level of functioning and disability were worse in this particular patient group. History of antipsychotic combination use prior to clozapine was found to predict the future use of clozapine augmentation. Conclusion: Adding a second antipsychotic seems to be the most common method of augmenting clozapine treatment in schizophrenia. The group of patients whose clozapine treatment is augmented appears to represent a "more difficult to treat" patient group before clozapine is initiated. [ABSTRACT FROM AUTHOR]

Introduction: Psychological support throughout psilocybin therapy is mandated by regulators as an essential part of ensuring participants' physical and psychological safety. There is an increased need for specially trained therapists who can provide high-quality care to participants in clinical studies. This paper describes the development and practical implementation of a therapist training program of psychological support within a current phase IIb international, multicenter, randomized controlled study of psilocybin therapy for people experiencing treatment-resistant depression. Description of Training Program: This new and manualized approach, based on current evidence-based psychotherapeutic approaches, was developed in partnership with different mental health researchers, practitioners, and experts; and has been approved by the FDA. Training consists of four components: an online learning platform; in-person training; applied clinical training; and ongoing individual mentoring and participation in webinars.This paper provides a brief overview of the method of support, the rationale and methodology of the training program, and describes each stage of training. The design and implementation of fidelity procedures are also outlined. Lessons Learned: As part of the phase IIb study of psilocybin therapy for treatment-resistant depression, 65 health care professionals have been fully trained as therapists and assisting therapists, across the US, Canada and Europe. Therapists provided informal feedback on the training program. Feedback indicates that the didactic and experiential interactive learning, delivered through a combination of online and in-person teaching, helped therapists build conceptual understanding and skill development in the therapeutic approach. Clinical training and engagement in participant care, under the guidance of experienced therapists, were considered the most beneficial and challenging aspects of the training. Conclusions: Clinical training for therapists is essential for ensuring consistently high-quality psilocybin therapy. Development of a rigorous, effective and scalable training methodology has been possible through a process of early, active and ongoing collaborations between mental health experts. To maximize impact and meet phase III and post-approval need, enhanced online learning and establishing pathways for clinical training are identified as critical points for quality assurance. This will require close public, academic and industry collaboration. [ABSTRACT FROM AUTHOR]

Background: The issue of treatment resistance in eating disorder care is controversial. Prior research has identified multiple failed treatment attempts as a common criterion for severe and enduring anorexia nervosa, but little is known about patients who have multiple failed treatment attempts. This study was designed to compare the clinical and demographic characteristics of eating disorder patients with multiple, incomplete inpatient admissions to those with good outcomes. Understanding if these patient populations differ at initial admissions has implications for the prediction and characterization of inpatient eating disorder treatment resistance. Methods: This study analyzed existing data from a specialist inpatient eating disorder program at a large Canadian teaching hospital collected between 2000 and 2016. Treatment resistance was defined as two or more incomplete admissions and no complete admissions in the study period. Data were available on 37 patients who met this criteria, and 38 patients who had completed their first admission and remained well (defined as a BMI > 18.5 with no binging or purging behavior) 1 year after discharge. Variables of interest included age, weight, diagnoses, duration of illness, eating disorder psychopathology, eating disorder behavioral frequencies and depressive symptoms at the time of index inpatient admissions. Statistical analyses consisted of Mann–Whitney U tests, Chi-square tests, and a logistic regression. Results: In our main bivariate analyses, patients with multiple incomplete admissions were characterized by more severe eating disorder psychopathology and depressive symptoms at admission as well as an increased prevalence of the binge purge subtype of anorexia nervosa. In our exploratory multivariate analyses controlling for diagnostic subtype and depressive symptoms, severity of eating disorder psychopathology did not remain significant. No statistically significant difference in body mass index (BMI) or frequencies of eating disorder behaviors were found. A trend toward a longer duration of illness did not meet statistical significance. Conclusions: This study found that patients considered resistant to inpatient eating disorder treatment differ from those with good outcomes at initial admission. These results suggest that while treatment-resistant anorexia nervosa may be related to severe and enduring anorexia nervosa, it may also be a different concept that warrants additional research. [ABSTRACT FROM AUTHOR]

Treatment-resistant schizophrenia, affecting approximately 20–30% of patients with schizophrenia, has a high burden both for patients and healthcare services. There is a need to identify treatment resistance earlier in the course of the illness, in order that effective treatment, such as clozapine, can be offered promptly. We conducted a systemic literature review of prospective longitudinal studies with the aim of identifying predictors of treatment-resistant schizophrenia from the first episode. From the 545 results screened, we identified 12 published studies where data at the first episode was used to predict treatment resistance. Younger age of onset was the most consistent predictor of treatment resistance. We discuss the gaps in the literature and how future prediction models can identify predictors of treatment response more robustly. [ABSTRACT FROM AUTHOR]

Objective: To examine the effect of esketamine nasal spray (ESK) plus newly initiated oral antidepressant (OAD) versus OAD plus placebo nasal spray (PBO) on the association between Montgomery-Åsberg Depression Rating Scale (MADRS) and 9-item Patient Health Questionnaire (PHQ-9) scores in adults with treatment-resistant depression (TRD)., Methods: Data from TRANSFORM-1 and TRANSFORM-2 (two similarly designed, randomized, active-controlled TRD studies) and SUSTAIN-1 (relapse prevention study) were analyzed. Group differences for mean changes in PHQ-9 total score from baseline were compared using analysis of covariance. Associations between MADRS and PHQ-9 total scores from TRANSFORM-1/TRANSFORM-2 were assessed using simple parametric, nonparametric, and multiple regression models., Results: In TRANSFORM-1/TRANSFORM-2 (ESK + OAD, n  = 343; OAD + PBO, n  = 222), baseline PHQ-9 mean scores were 20.4 for ESK + OAD and 20.6 for OAD + PBO (severe depression). At day 28, significant group differences were observed in least squares mean change (SE) in PHQ-9 scores from baseline (-12.8 [0.46] vs -10.3 [0.53], P  < .001) and in clinically substantial change in PHQ-9 scores (≥6 points; 77.1% vs 64%, P  < .001) in ESK + OAD and OAD + PBO groups, respectively. A nonlinear relationship between MADRS and PHQ-9 was observed; total scores demonstrated increased correlation over time. In SUSTAIN-1, 57.3% of patients receiving ESK + OAD ( n  = 89) versus 44.2% receiving OAD + PBO ( n  = 86) retained remission status (PHQ-9 score ≤4) at maintenance treatment end point ( P =  .044)., Conclusions: In adults with TRD, ESK + OAD significantly improved severity of depressive symptoms, and more patients achieved clinically meaningful changes in depressive symptoms based on PHQ-9, versus OAD + PBO. PHQ-9 outcomes were consistent with those of clinician-rated MADRS., Trial Registration: ClinicalTrials.gov: NCT02417064, NCT02418585, NCT02493868.

Functional connectivity resting-state functional magnetic resonance imaging has been proposed to predict antipsychotic treatment response in schizophrenia. However, only a few prospective studies have examined baseline resting-state functional magnetic resonance imaging data in drug-naïve first-episode schizophrenia patients with regard to subsequent treatment response. Data-driven approaches to conceptualize and measure functional connectivity patterns vary broadly, and model-free, voxel-wise, whole-brain analysis techniques are scarce. Here, we apply such a method, called connectivity concordance mapping to resting-state functional magnetic resonance imaging data acquired from an Asian sample ( n = 60) with first-episode psychosis, prior to pharmaceutical treatment. Using a longitudinal design, 12 months after the resting-state functional magnetic resonance imaging, we measured and classified patients into two groups based on psychometric testing: treatment responsive and treatment resistant. Next, we compared the two groups' connectivity concordance maps that were derived from the resting-state functional magnetic resonance imaging data at baseline. We have identified consistently higher functional connectivity in the treatment-resistant group in a network including the left hippocampus, bilateral insula and temporal poles. These data-driven novel findings can help researchers to consider new regions of interest and facilitate biomarker development in order to identify treatment-resistant schizophrenia patients early, in advance of treatment and at the time of their first psychotic episode., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

This Mini-Review presents recent research into evidence for psychological treatments for people with severe and enduring anorexia nervosa (SEAN). Two psychological therapies, specialist supportive clinical management (SSCM), and cognitive behavior therapy for anorexia nervosa (CBT-AN) have limited (one randomized controlled study) evidence of efficacy. Both have had adaptations for SEAN, notably with revision of the primary treatment goal of improved quality of life and full weight recovery a secondary goal. A major issue with existing studies is poor definition of SEAN, and the large deficit in research that has used an agreed definition of SEAN. In particular, it may be problematic to extrapolate from studies of people with either severe and/or enduring but not intractable or “resistant” illness. People with longstanding AN who have not received evidence based care should be offered this with an expectation of recovery. Similarly, people with SEAN may be offered care with judicious mitigation of expectations. In the future, trials should include people with SEAN clearly defined. Trials with a subsample of participants likely to have SEAN, if identified at randomisation, are an opportunity for secondary analyses of such participants. This would widen the evidence base for psychological treatments providing hope for people with this devastating illness. Finally, there is an urgent need not only to strengthen our existing knowledge with studies of sufficient power, but also, fundamentally, to derive novel conceptualizations of what “treatment” involves.

BackgroundOff-label ketamine treatment has shown acute antidepressant effects that offer hope for patients with therapy-resistant depression. However, its potential for integration into treatment algorithms is controversial, not least because the evidence base for maintenance treatment with repeated ketamine administration is currently weak. Ketamine is also a drug of misuse, which has raised concerns regarding the target population. Little is known about which patients would seek ketamine treatment if it were more widely available.AimsTo explore some of the characteristics of the patients actively seeking ketamine treatment.MethodAn online survey containing questions about duration of current depressive episode, number of antidepressants used and other comments was completed by patients who were exploring the internet regarding the possibility of ketamine for depression.ResultsOf the 1088 people who registered their interest, 93.3% reported depression, 64.3% reported a chronic course of their symptoms and in the past 10 years, 86.3% had tried at least two antidepressants. Desperation was a common theme, but this appeared to be competently expressed. A small minority (