Citations

Summary The American Society of Clinical Psychopharmacology convened a 45-member international expert task force to identify circumstances supporting the deprescribing of core psychotropic medications for major depressive disorder (MDD) and bipolar disorders. Three Delphi survey rounds plus a selective literature review identified points of consensus (predefined as ≥75% agreement) about when antidepressant, antipsychotic, mood stabiliser and sedative-hypnotic deprescribing is warranted. Twenty out of 32 statements (63%) achieved consensus across seven thematic areas. In MDD, panellists favoured discontinuing antidepressants when mechanisms of action are duplicative, adequate trials produce ≤25% improvement or loss of prior efficacy cannot be regained through dose increases or augmentations. Indefinite antidepressant maintenance in MDD was favoured after three or more lifetime episodes. In bipolar disorder, antidepressant deprescribing was favoured in the setting of rapid cycling, mixed features or emerging mania/hypomania symptoms; and discouraged if prior antidepressant cessation led to relapse. In nonpsychotic mood disorders, panellists favoured deprescribing antipsychotics that caused significant weight gain or tardive dyskinesia over adding pharmacological antidotes. Deprescribing to achieve an eventual medication-free status was considered inappropriate, in bipolar type 1, but not necessarily bipolar type 2 disorder. Although individualised circumstances necessarily inform psychopharmacology management, clinical presentations that misalign with existing pharmacotherapies may signal the desirability of cautious deprescribing.

While the clinical focus on the sentinel lymph node biopsy (SLNB) is the presence of intra- or extra-nodal metastases, preclinical studies suggest that tumor-draining SLNB-associated vascular architecture and adhesion properties are altered regardless of SLNB positivity. Human intravital microscopy (HIVM) has defined blood vessel abnormalities that may impact lymphocyte adhesion and systemic drug delivery at primary melanoma sites. In this pilot study of HIVM during melanoma SLNB, we sought to determine the feasibility of obtaining HIVM observations of SLNB-associated vessels. We successfully performed HIVM in all 20 SLNB patients, and 7 were found to have nodal micrometastases by standard pathology. HIVM was capable of identifying both functional and non-functional SLNB-associated vessels based on the presence or absence of fluorescent dye uptake, respectively. Comparing vessel characteristics as a secondary exploratory objective, no statistically significant differences were noted in the diameter, flow rate, functionality, or shear stress of SLNB-associated blood vessels between positive and negative SLNBs, which may likely have been a reflection of the minimal disease burden. Nonetheless, these initial observations provide the framework to optimize future trials of HIVM in cancer patients.

Importance There is a need for greater recognition of clinical psychopharmacology endpoints, including instances where specific psychotropic medications may become unnecessary, redundant, contradictory, or otherwise inappropriate and therefore merit deprescribing. Objective To address circumstances warranting psychotropic medication deprescribing. Evidence Review The American Society of Clinical Psychopharmacology convened a panel of 45 international psychopharmacology experts who developed and completed a multiround Delphi survey and conducted a focused literature review between January and May of 2025, in order to identify areas of consensus or disagreement on key aspects of the deprescribing of psychotropic medications. These included collaborative risk-benefit assessments with patients; pharmacokinetic and pharmacodynamic factors; pharmacogenomics; distinguishing redundant or conflictual from complementary mechanisms of action; managing adverse effects; assuring medication adherence; drug tolerance or tachyphylaxis; medication misuse; and the psychological context and ramifications of deprescribing. Findings Consensus was achieved on 44 of 50 final Delphi statements (88%). Panelists unanimously agreed that components of a pharmacotherapy regimen should undergo periodic review to ensure that treatments target relevant symptoms and have favorable risk-benefit ratios. Key points of consensus were that deprescribing: (1) should not occur without first assessing medication adherence; (2) merits consideration if less than partial therapeutic response is apparent, or if treatment goals have been reached and relapse prevention is not a long-term objective; (3) involves psychological ramifications that warrant attention; (4) should be followed by close clinical monitoring; and (5) risk-benefit decisions should ideally involve active patient participation within a shared decision-making model. Conclusions and Relevance Through this Consensus Statement, the Task Force identified circumstances in which the selective elimination of certain psychotropic medications may be clinically indicated. Empirical trials are needed to assess the implementation of deprescribing protocols and gauge their safe, effective, and acceptable outcomes.

The treatment landscape for soft tissue sarcomas (STS) is evolving constantly. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for STS specific to surgical management and systemic therapy recommendations for various subtypes.

Abstract While the clinical focus on the sentinel lymph node biopsy (SLNB) is the presence of intra- or extra-nodal metastases, preclinical studies suggest that tumor-draining SLNB-associated vascular architecture and adhesion properties are altered regardless of SLNB positivity. Human intravital microscopy (HIVM) has defined blood vessel abnormalities that may impact lymphocyte adhesion and systemic drug delivery at primary melanoma sites. In this pilot study of HIVM during melanoma SLNB, we sought to determine the feasibility of obtaining HIVM observations of SLNB-associated vessels. We successfully performed HIVM in all 20 SLNB patients, and 7 were found to have nodal micrometastases by standard pathology. HIVM was capable of identifying both functional and non-functional SLNB-associated vessels based on the presence or absence of fluorescent dye uptake, respectively. Comparing vessel characteristics as a secondary objective, no statistically significant differences were noted in the diameter, flow rate, functionality, or shear stress of SLNB-associated blood vessels between positive and negative SLNBs, which may likely have been a reflection of the minimal disease burden. Nonetheless, these initial observations provide the framework to optimize future trials of HIVM in cancer patients.

Abstract Purpose/Background Clozapine was approved in the United States (US) using 1989 regulations and knowledge. After 30 years, many sections of the US package insert (PI) are outdated. Methods We comprehensively reviewed the literature to propose PI updates. We present the information in 2 articles. In Part I, we focus on basic pharmacology based on 407 relevant articles. Part II focuses on clinical aspects and pharmacovigilance. Findings/Results Based on more recent expectations of Food and Drug Administration regulations, we reviewed clozapine basic pharmacology including the following: 1) clearance, 2) pharmacokinetics and pharmacodynamics, and 3) monitoring tools. We identified 9 major problems in the basic pharmacological sections of the PI including the following: 1) in vivo studies indicate that clozapine is dependent on CYP1A2 for its metabolism, 2) the minor role of CYP2D6 in clozapine metabolism requires removing the PI recommendation to lower clozapine doses in CYP2D6 poor metabolizers, 3) in nontoxic concentrations CYP3A4 has a minor role in clozapine metabolism and potent CYP3A4 inhibitors lack clinically relevant effects, 4) several drug-drug interactions need to be updated based on recent literature, 5) systemic inflammation may decrease clozapine metabolism and increase the risk of clozapine intoxication, 6) obesity may decrease clozapine metabolism, 7) patients of Asian and Indigenous American ancestry need lower clozapine doses, 8) personalized titration and c-reactive protein monitoring should be considered until prospective studies are available, and 9) the half-life section needs to be modified to acknowledge that single dosing at night is frequent in the US. Implications/Conclusions An improvement in the US clozapine PI may lead to improvement in PIs worldwide.

Abstract Purpose/Background This is the second part of a 2-part article that proposes improving the United States (US) clozapine package insert. Part II focuses on fatal outcomes and the 5 boxed warnings, 4 specifically for clozapine: severe neutropenia, seizure, orthostatic hypotension and myocarditis, and 1 for all antipsychotics (elderly with dementia). Methods US reports to the World Health Organization's global pharmacovigilance database were analyzed from clozapine's introduction to January 15, 2023. Findings/Results The US was the top reporter worldwide for clozapine with 56,003 reports and 9587 associated fatal outcomes. The 4 clozapine boxed warnings were associated with 534 fatal outcomes (218 with severe neutropenia, 131 with seizures, 125 with orthostasis, 36 with myocarditis, 24 with cardiomyopathy, and 0 with mitral valve prolapse). With no boxed warnings, pneumonia was associated with 674 fatal outcomes and increased white blood cell count (a sign of infection) with 596 fatal outcomes. After considering overlaps, pneumonia and increases in white blood cell count explained 900 fatalities, or 9.4% of 9587 fatal outcomes. The Food and Drug Administration continues to focus on severe neutropenia which was associated with only 218 or 2.3% of fatal outcomes, whereas 97.7% of fatal outcomes reported in US clozapine-treated patients had another cause. Implications/Conclusions To help prevent future deaths in clozapine-treated patients, the clozapine package insert should focus on fatal outcomes during infections. Part II offers detailed solutions regarding current boxed warnings and lack of a warning for pneumonia and other infections. The Supplementary Material includes letters of support from 124 non-US clozapine experts from 44 countries/regions who support Parts I and II.

Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.

Soft tissue sarcomas (STS) are rare malignancies of mesenchymal cell origin that display a heterogenous mix of clinical and pathologic characteristics. STS can develop from fat, muscle, nerves, blood vessels, and other connective tissues. The evaluation and treatment of patients with STS requires a multidisciplinary team with demonstrated expertise in the management of these tumors. The complete NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Soft Tissue Sarcoma provide recommendations for the diagnosis, evaluation, and treatment of extremity/superficial trunk/head and neck STS, as well as retroperitoneal/intra-abdominal STS, desmoid tumors, and rhabdomyosarcoma. This portion of the NCCN Guidelines discusses general principles for the diagnosis and treatment of retroperitoneal/intra-abdominal STS, outlines treatment recommendations, and reviews the evidence to support the guidelines recommendations.