UNASSIGNED: Over the past decade, glutamate has emerged as a prominent focus in the field of obsessive-compulsive disorder (OCD) pathophysiology. A convergence of evidence from genetic, preclinical, and clinical studies points to glutamatergic dysfunction as a key feature of this condition. In light of these findings, there has been a growing interest in exploring the potential of glutamatergic agents in the treatment of OCD.
UNASSIGNED: This paper reviews the literature on glutamate transmission in OCD. In addition, the authors examine the results of clinical trials investigating the efficacy of glutamatergic agents in the treatment of OCD patients.
UNASSIGNED: Along with the recognition of neuroinflammation in the brain in OCD, the evidence of glutamate dysfunction represents one of the most promising recent discoveries for understanding the mechanisms involved in OCD. The importance of this discovery lies primarily in its pharmacological implications and has led to intense research activity in the field of glutamatergic agents. While this research has not yet had a substantial clinical impact, targeting glutamate receptors remains a promising horizon for the successful treatment of OCD patients.

UNASSIGNED: Schizophrenia (SCZ) and autism spectrum disorder (ASD) are neurodevelopmental diseases characterized by different psychopathological manifestations and divergent clinical trajectories. Various alterations at glutamatergic synapses have been reported in both disorders, including abnormal NMDA and metabotropic receptor signaling.
UNASSIGNED: We conducted a bicentric study to assess the blood serum levels of NMDA receptors-related glutamatergic amino acids and their precursors, including L-glutamate, L-glutamine, D-aspartate, L-aspartate, L-asparagine, D-serine, L-serine and glycine, in ASD, SCZ patients and their respective control subjects. Specifically, the SCZ patients were subdivided into treatment-resistant and non-treatment-resistant SCZ patients, based on their responsivity to conventional antipsychotics.
UNASSIGNED: D-serine and D-aspartate serum reductions were found in SCZ patients compared to controls. Conversely, no significant differences between cases and controls were found in amino acid concentrations in the two ASD cohorts analyzed.
UNASSIGNED: This result further encourages future research to evaluate the predictive role of selected D-amino acids as peripheral markers for SCZ pathophysiology and diagnosis.

There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches.

Repetitive transcranial magnetic stimulation (rTMS) therapy could be improved by better and earlier prediction of response. Latent class mixture (LCMM) and non-linear mixed effects (NLME) modelling have been applied to model the trajectories of antidepressant response (or non-response) to TMS, but it is not known whether such models can predict clinical outcomes. We compared LCMM and NLME approaches to model the antidepressant response to TMS in a naturalistic sample of 238 patients receiving rTMS for treatment resistant depression (TRD), across multiple coils and protocols. We then compared the predictive power of those models. LCMM trajectories were influenced largely by baseline symptom severity, but baseline symptoms provided little predictive power for later antidepressant response. Rather, the optimal LCMM model was a nonlinear two-class model that accounted for baseline symptoms. This model accurately predicted patient response at 4 weeks of treatment (AUC = 0.70, 95% CI = [0.52-0.87]), but not before. NLME offered slightly improved predictive performance at 4 weeks of treatment (AUC = 0.76, 95% CI = [0.58 - 0.94], but likewise, not before. In showing the predictive validity of these approaches to model response trajectories to rTMS, we provided preliminary evidence that trajectory modeling could be used to guide future treatment decisions.

BACKGROUND: Up to 34% of patients with schizophrenia are resistant to several treatment trials. Lack of continuous and adequate treatment is associated with relapse, rehospitalization, a lower effect of antipsychotic therapy, and higher risk of side effects. Long-acting injectables antipsychotics (LAI APs) enhance compliance and improve clinical outcomes and quality of life in patients with schizophrenia, and thus it may be advisable to administer two LAI APs at the same time in cases of treatment-resistant schizophrenia. The purpose of this review is to summarize the available literature regarding the combined use of two LAI APs in patients with schizophrenia or other psychotic spectrum disorders.
METHODS: An extensive literature search for relevant articles regarding any combination of two long-acting injectable antipsychotics has been performed from inception up to 9 February 2024, on PubMed, Scopus and APA PsycInfo, according to the PRISMA statement. Only studies reporting combination of two LAI APs and its clinical outcome in patients with schizophrenia and related disorders were selected.
RESULTS: After the selection process, nine case reports, four case series and two observational retrospective studies were included in the final analysis. All patients treated with dual LAI APs reported a good response, and no new or unexpected adverse effects due to the combination of two LAIs were reported. Different drug combinations were used, and the most frequent association resulted in aripiprazole monohydrate + paliperidone palmitate once monthly (32 times).
CONCLUSIONS: Our review highlights that the treatment regimen with two concurrent LAI APs is already widely used in clinical practice and is recognized as providing a promising, effective, and relatively safe therapeutic strategy for treating the schizophrenia spectrum disorders.

Post-transplantation cyclophosphamide (PTCy) following hematopoietic cell transplantation (HCT) has emerged as standard of care for graft-versus-host disease (GVHD) prevention in adult patients without increasing malignant relapse. We previously defined acute GVHD (aGVHD) treatment response categories as corticosteroid-sensitive (SS), -dependent (SD), or -resistant (SR) based on response to first-line corticosteroids and reported their clinical outcomes following non-PTCy-based prophylaxis. More than one-third of patients developed aGVHD necessitating systemic therapy. Cases were predominantly SR, with a 14% overall incidence of SR aGVHD. The incidence and clinical outcomes of these 3 distinct aGVHD treatment response groups following PTCy-based prophylaxis have not been well described. The objective of this retrospective single-institution cohort study was to assess the incidence and clinical outcomes of SS, SD, and SR aGVHD following HCT with PTCy-based prophylaxis using a prophylactic regimen of PTCy, tacrolimus, and mycophenolate mofetil (MMF). We included 196 consecutive adult and pediatric patients undergoing allogeneic HCT for malignant and non-malignant disorders at the University of Minnesota between 2017 and 2021. Patients received PTCy on days +3 and +4 plus tacrolimus and MMF prophylaxis. Bone marrow and peripheral blood stem cell graft sources and related and unrelated donors were included. Recipients received myeloablative or reduced-intensity conditioning regimens. Of the 196 allografts, 54 (28%) developed aGVHD before day +180, with a median time to onset of 50 days (interquartile range, 34 to 71 days). Of those, 32 patients (16% overall) developed maximum grade II-III aGVHD necessitating systemic corticosteroids, with the following response: 13 SS (41%), 10 SD (31%), and 9 SR (28%). The overall incidence of SR aGVHD was 4.6%. Only 12 patients (6%) developed maximum grade III aGVHD, and none had grade IV aGVHD. The 2-year overall survival analyzed from 80 days after initiation of systemic treatment was similar in the SS and SD groups (77 and 75%, respectively), comparable to those without aGVHD (81%), and was lowest in the SR group (20%), with GVHD the primary cause of death. Nonrelapse mortality was highest in the SR group. MN high-risk and higher GVHD grade at onset were risk factors for developing SR aGVHD. Overall, we report a low incidence (16%) of aGVHD requiring systemic corticosteroids with PTCy-based prophylaxis. aGVHD cases were predominantly SS aGVHD, with lower incidences of SD and SR aGVHD. Our findings suggest that PTCy-based prophylaxis reduces the rate of treatment-resistant aGVHD. Patients with SR aGVHD had the worst clinical outcomes and poorest survival. Those with SS and SD aGVHD had similar clinical outcomes, both better than seen with SR aGVHD.

This study aimed to evaluate the association of the six parameters, namely stimulation intensity, stimulation frequency, pulses per session, treatment duration, number of sessions, and total number of pulses with the efficacy of conventional transcranial magnetic stimulation (rTMS) over left dorsolateral prefrontal cortex for patients with treatment-resistant depression (TRD). A random-effects dose-response meta-analysis of blinded randomized controlled trials (RCTs) involving 2391 participants were conducted to examine the dose-effect relationship of six stimulation parameters. Any of the six parameters significantly individually predicted proportion of variance in efficacy: pulses per session (R²=52.7%), treatment duration (R²=51.2%), total sessions (R²=50.9%), frequency (R²=49.6%), total pulses (R²=49.5%), and intensity (R²= 40.4%). Besides, we identified frequency as a potential parameter interacting with the other five parameters, resulting in a significant increase in variance(ΔR2) ranging from 5.0% to 16.7%. Finally, we found that RCTs using frequency > 10 Hz compared to those of 10 Hz showed better dose-effect relationships. We conclude that the six stimulation parameters significantly predict the dose-effect relationship of conventional rTMS on TRD. Besides, higher stimulation frequency, higher stimulation intensity, and adequate number of pulses were associated with treatment efficacy.

OBJECTIVE: To investigate whether the association between depression and inflammatory joint disease (IJD; rheumatoid arthritis [RA], psoriatic arthritis [PsA], ankylosing spondylitis/spondyloarthropathies [AS], and juvenile idiopathic arthritis [JIA]) is affected by the severity or treatment-resistance of depression.
METHODS: Parallel cohort studies and case-control studies among 600,404 patients with a depressive episode identified in Swedish nationwide administrative registers. Prospective and retrospective risk for IJD in patients with depression was compared to matched population comparators, and the same associations were investigated in severe or treatment-resistant depression. Analyses were adjusted for comorbidities and sociodemographic covariates.
RESULTS: Patients with depression had an increased risk for later IJD compared to population comparators (adjusted hazard ratio (aHR) for any IJD 1.34 [95% CI 1.30-1.39]; for RA 1.27 [1.15-1.41]; PsA 1.45 [1.29-1.63]; AS 1.32 [1.15-1.52]). In case-control studies, patients with depression more frequently had a history of IJD compared to population controls (adjusted odds ratio (aOR) for any IJD 1.43 [1.37-1.50]; RA 1.39 [1.29-1.49]; PsA 1.59 [1.46-1.73]; AS 1.49 [1.36-1.64]; JIA 1.52 [1.35-1.71]). These associations were not significantly different for severe depression or TRD.
CONCLUSIONS: IJD and depression are bidirectionally associated, but this association does not seem to be influenced by the severity or treatment resistance of depression.

OBJECTIVE: This study aims to explore the outcome with iv ketamine treatment in a real-world clinical setting, primarily measured as posttreatment days hospitalised.
METHODS: The psychiatric medical records of 46 patients having received iv ketamine on a psychiatric treatment indication between 2015 and 2018 were retrospectively examined. Analysis comparing the number and duration of hospital admissions before and after ketamine treatment as well as logistic regression analysis to investigate clinical predictors of effectiveness, were performed. To assess patients\' severity of depressed symptoms records were screened for MADRS-S scores.
RESULTS: No significant difference between pre- and posttreatment hospital days (p = 0.170), or number of hospitalisations (p = 0.740) were found. The response rate was 31% and remission rate 21%. None of the predictors showed statistical significance in the logistic model.
CONCLUSIONS: Iv ketamine treatment showed effectiveness in reducing depressive symptoms even with complex patients in a real-world clinical setting. However, this did not translate to a reduction in hospitalisation. Highlighting the multifaceted challenges posed when implementing iv ketamine treatment in clinical practice.

Clozapine, amongst antipsychotics, has a unique composite mode of action that might translate into an expanded therapeutic potential on clinical grounds. Sorely, clozapine remains underutilized.