Predicting Conversion to Insulin Sensitivity With Metformin: A Promising Tool for Clinicians in Addressing Insulin Resistance and Improving Outcomes in Patients With Treatment Resistant Bipolar Depression.

BACKGROUND: Insulin resistance (IR) changes the trajectory of responsive bipolar disorder to a treatment-resistant course. A clinical trial conducted by our group demonstrated that IR reversal by metformin improved clinical and functional outcomes in treatment-resistant bipolar depression (TRBD). To aid clinicians identify which metformin-treated TRBD patients might reverse IR, and given strong external evidence for their association with IR, we developed a predictive tool using body mass index (BMI) and homeostatic model assessment-insulin resistance (HOMA-IR). METHODS: The predictive performance of baseline BMI and HOMA-IR was tested with a logistic regression model using known metrics: area under the receiver operating curve, sensitivity, and specificity. In view of the high benefit to low risk of metformin in reversing IR, high sensitivity was favored over specificity. RESULTS: In this BMI and HOMA-IR model for IR reversal, the area under the receiver operating curve is 0.79. At a cutoff probability of conversion of 0.17, the model's sensitivity is 91% (95% confidence interval [CI], 57%-99%), and the specificity is 56% (95% CI, 36%-73%). For each unit increase in BMI or HOMA-IR, there is a 15% (OR, 0.85; 95% CI, 0.71-0.99) or 43% (OR, 0.57; CI, 0.18-1.36) decrease in the odds of conversion, respectively. CONCLUSIONS: In individuals with TRBD, this tool using BMI and HOMA-IR predicts IR reversal with metformin with high sensitivity. Furthermore, these data suggest early intervention with metformin at lower BMI, and HOMA-IR would likely reverse IR in TRBD.

Variation of Clozapine Use for Treatment of Schizophrenia: Evidence from Pennsylvania Medicaid and Dually Eligible Enrollees.

While clozapine is the most effective antipsychotic treatment for treatment-resistant schizophrenia, it remains underutilized across the United States, warranting a more comprehensive understanding of variation in use at the county level, as well as characterization of existing prescribing patterns. Here, we examined both Medicaid and Medicare databases to (1) characterize temporal and geographic variation in clozapine prescribing and, (2) identify patient-level characteristics associated with clozapine use. We included Medicaid and Fee for Service Medicare data in the state of Pennsylvania from January 1, 2013, through December 31, 2019. We focused on individuals with continuous enrollment, schizophrenia diagnosis, and multiple antipsychotic trials. Geographic variation was examined across counties of Pennsylvania. Regression models were constructed to determine demographic and clinical characteristics associated with clozapine use. Out of 8,255 individuals who may benefit from clozapine, 642 received treatment. We observed high medication burden, overall, including multiple antipsychotic trials. We also identified variation in clozapine use across regions in Pennsylvania with a disproportionate number of prescribers in urban areas and several counties with no identified clozapine prescribers. Finally, demographic, and clinical determinants of clozapine use were observed including less use in people identified as non-Hispanic Black, Hispanic, or with a substance use disorder. In addition, greater medical comorbidity was associated with increased clozapine use. Our work leveraged both Medicaid and Medicare data to characterize and surveil clozapine prescribing. Our findings support efforts monitor disparities and opportunities for the optimization of clozapine within municipalities to enhance clinical outcomes.

Ablative and Immunostimulatory Effects of Histotripsy Ablation in a Murine Osteosarcoma Model.

Background: Osteosarcoma (OS) is the most frequently occurring malignant bone tumor in humans, primarily affecting children and adolescents. Significant advancements in treatment options for OS have not occurred in the last several decades, and the prognosis remains grim with only a 70% rate of 5-year survival. The objective of this study was to investigate the focused ultrasound technique of histotripsy as a novel, noninvasive treatment option for OS. Methods: We utilized a heterotopic OS murine model to establish the feasibility of ablating OS tumors with histotripsy in a preclinical setting. We investigated the local immune response within the tumor microenvironment (TME) via immune cell phenotyping and gene expression analysis. Findings: We established the feasibility of ablating heterotopic OS tumors with ablation characterized microscopically by loss of cellular architecture in targeted regions of tumors. We observed greater populations of macrophages and dendritic cells within treated tumors and the upregulation of immune activating genes 72 h after histotripsy ablation. Interpretation: This study was the first to investigate histotripsy ablation for OS in a preclinical murine model, with results suggesting local immunomodulation within the TME. Our results support the continued investigation of histotripsy as a novel noninvasive treatment option for OS patients to improve clinical outcomes and patient prognosis.

Applying Shared Decision Making to the Process of Medication Deprescribing in Schizophrenia.

Deprescribing, the identification and discontinuation of medications that are no longer indicated or that cause adverse effects that outweigh clinical benefit, relies on the integration of clinical expertise and patient values using shared decision making (SDM). This case series describes the application of SDM to the process of deprescribing in patients with serious mental illness, illustrating the ways in which SDM builds a therapeutic alliance between patient, psychiatrist, family members, and other health care professionals to collaboratively develop treatment plans.

Community-Based Service Use After Clozapine Treatment: A Mirror-Image Analysis of Public Claims Data.

Although clozapine demonstrates unique efficacy for treatment-resistant schizophrenia, its impact on community-based services remains largely underexplored. The authors examined changes in use of community-based services after clozapine treatment among a sample of 163 patients with schizophrenia by using public claims data in Allegheny County, Pennsylvania. Mirror-image analyses of service utilization were used to compare the 180-day period before treatment initiation with the 180-day period that began after 6 months of adherent treatment, accounting for age, race, and gender. Across demographic variables, clozapine treatment was associated with increased use of community-based services and decreased use of psychiatric inpatient services (p<0.05, Bonferroni corrected), suggesting that clozapine treatment shifts service needs from emergency care to community-based care and recovery.

Characterizing the Ablative Effects of Histotripsy for Osteosarcoma: In Vivo Study in Dogs.

Osteosarcoma (OS) is a malignant bone tumor treated by limb amputation or limb salvage surgeries and chemotherapy. Histotripsy is a non-thermal, non-invasive focused ultrasound therapy using controlled acoustic cavitation to mechanically disintegrate tissue. Recent ex vivo and in vivo pilot studies have demonstrated the ability of histotripsy for ablating OS but were limited in scope. This study expands on these initial findings to more fully characterize the effects of histotripsy for bone tumors, particularly in tumors with different compositions. A prototype 500 kHz histotripsy system was used to treat ten dogs with suspected OS at an intermediate treatment dose of 1000 pulses per location. One day after histotripsy, treated tumors were resected via limb amputation, and radiologic and histopathologic analyses were conducted to determine the effects of histotripsy for each patient. The results of this study demonstrated that histotripsy ablation is safe and feasible in canine patients with spontaneous OS, while offering new insights into the characteristics of the achieved ablation zone. More extensive tissue destruction was observed after histotripsy compared to that in previous reports, and radiographic changes in tumor size and contrast uptake following histotripsy were reported for the first time. Overall, this study significantly expands our understanding of histotripsy bone tumor ablation and informs future studies for this application.

Histotripsy Ablation of Spontaneously Occurring Canine Bone Tumors In Vivo.

OBJECTIVE: Osteosarcoma (OS) is a devastating primary bone tumor in dogs and humans with limited non-surgical treatment options. As the first completely non-invasive and non-thermal ablation technique, histotripsy has the potential to significantly improve the standard of care for patients with primary bone tumors. INTRODUCTION: Standard of care treatment for primary appendicular OS involves surgical resection via either limb amputation or limb-salvage surgery for suitable candidates. Biological similarities between canine and human OS make the dog an informative comparative oncology research model to advance treatment options for primary OS. Evaluating histotripsy for ablating spontaneous canine primary OS will build a foundation upon which histotripsy can be translated clinically into a standard of care therapy for canine and human OS. METHODS: Five dogs with suspected spontaneous OS were treated with a 500 kHz histotripsy system guided by real-time ultrasound image guidance. Spherical ablation volumes within each tumor (1.25-3 cm in diameter) were treated with single cycle histotripsy pulses applied at a pulse repetition frequency of 500 Hz and a dose of 500 pulses/point. RESULTS: Tumor ablation was successfully identified grossly and histologically within the targeted treatment regions of all subjects. Histotripsy treatments were well-tolerated amongst all patients with no significant clinical adverse effects. Conclusion & Significance: Histotripsy safely and effectively ablated the targeted treatment volumes in all subjects, demonstrating its potential to serve as a non-invasive treatment modality for primary bone tumors.

From Office-Based Treatment to Telehealth: Comparing Clinical Outcomes and Patient Participation in a Psychiatric Intensive Outpatient Program with a Large Transdiagnostic Sample.

Introduction: Patient participation and clinical outcomes of a precoronavirus disease 2019 (COVID-19) office-based transdiagnostic psychiatric intensive outpatient program (IOP) were compared with those of telehealth IOP during COVID-19. Materials and Methods: Weeks of enrollment, Patient Health Questionnaire-9 (PHQ-9) and Generalized Anxiety Disorder-7 (GAD-7) assessments, and sociodemographic and clinical factors (including group track and diagnosis) were collected during pre-COVID-19 (n = 191) and during COVID-19 (n = 200). Continuous and categorical measures of GAD-7 and PHQ-9 were analyzed; potential sociodemographic and clinical covariates to scores were also explored. Results: There were no statistically significant differences in participation between time periods. Associations were observed between PHQ-9/GAD-7 score improvement and number of assessments. Significant score reductions occurred in both periods, and differences in change scores were not significant. Sociodemographic and clinical factors were not significantly different between time periods. Patients with commercial insurance had significantly higher improvement in both mean and categorical PHQ-9 scores (t = 2.77, p = 0.006; χ2 = 10.47, df = 1, p = 0.001) and GAD-7 scores (t = 2.29, p = 0.023; χ2 = 8.58, df = 1, p = 0.003) than those with public insurance. Patients with anxiety disorders had significantly greater improvements (F = 4.49, p = 0.004; χ2 = 9.15, df = 3, p = 0.027) in GAD-7 during COVID-19. Discussion: Significant improvements in PHQ-9/GAD-7 scores and measures of participation were not significantly different between telehealth and office-based IOP, nor were they greatly influenced by clinical or sociodemographic factors. Further study is needed of possible care disparities for publicly insured patients. Conclusion: Despite some limitations, telehealth IOP appears to be a clinically appropriate option for a diverse sociodemographic and diagnostically heterogeneous psychiatric population.

Less is more: Deprescribing anticholinergic medications in persons with severe mental illness.

BACKGROUND: Long-term prescribing of anticholinergic medications (ACM) for antipsychotic-associated extrapyramidal symptoms (EPS) is not recommended, yet is widely prevalent. Adverse effects of ACM include memory impairment, dry mouth, constipation, blurred vision, urinary retention, and tachycardia, which can seriously impact quality of life. This quality improvement deprescription project sought to reduce chronic ACM use in patients with serious mental illness (SMI). METHODS: Education directed at psychiatrists combined with clinical pharmacy support for deprescription was used to target clinically stable patients diagnosed with schizophrenia, schizoaffective disorder, or bipolar disorder with no EPS and ACM prescriptions of ≥6 months. Scales were used to assess anticholinergic adverse effects, memory impairment, and quality of life. ACMs were tapered and discontinued over 1 to 6 months. RESULTS: More than 75% of targeted patients successfully tapered or discontinued ACM, which coincided with significant improvements in anticholinergic adverse effects, memory impairment, and quality of life. Approximately 10% of patients were restarted on ACM for re-emergent EPS. CONCLUSIONS: For most clinically stable patients with SMI without EPS, our findings suggest that gradual deprescription of chronic ACM is clinically appropriate, well tolerated, and improves quality of life. A randomized trial could provide more definitive answers.

Rapid expansion of direct-to-consumer telemental health during the COVID-19 pandemic: A case series.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic brought many challenges to patient care delivery. The need for social distancing and relaxing of federal and state telemental health regulations paved the way for widespread adoption of direct-to-consumer (DTC) ambulatory mental health video visits. METHODS: We present cases that demonstrate the use of video visits across 6 clinical areas, each serving a unique population of patients, in a large behavioral health system. The benefits and limitations of this modality are illustrated in children, adults, and older adults with mood disorders, anxiety disorders, intellectual disability, substance use disorders, neurocognitive disorders, and schizophrenia. RESULTS: Although telephone visits were acceptable and necessary to serve some patients, there are many advantages to video visits in providing best patient care. Education and support for telemental health-delivered to both patients and clinicians-is critical to the success of the DTC model. CONCLUSIONS: DTC telemental health is a widespread clinical tool used during the COVID-19 pandemic. Because this model has many strengths and advantages compared with traditional telemental health delivered in a clinic, regulators and insurers should be open to its continued use postpandemic when clinically appropriate.

Group teletherapy for first-episode psychosis: Piloting its integration with coordinated specialty care during the COVID-19 pandemic.

Digital health has emerged in recent years as a tool to optimize care delivery and promote treatment adherence among individuals with first-episode psychosis (FEP). Recent mandates for social distancing and sheltering in place due to the COVID-19 pandemic have catapulted efforts to provide ongoing coordinated specialty care (CSC) on virtual platforms. While prior evidence provides support for the general implementation of virtual individual therapy, there is limited guidance and evidence for the adoption of group teletherapy. Here we describe our efforts to implement group teletherapy for two small cohorts of individuals with FEP receiving care in a coordinated specialty care clinic using methods adopted from Acceptance and Commitment Therapy. We observed high adherence with group visits as well as client satisfaction across groups. Based on our results, we have taken efforts to implement virtual group therapy more permanently in our clinic. Our experience provides guidance and a model for integration of virtual group therapy within CSC. PRACTITIONER POINTS: In-person group therapy can be adapted as an online treatment modality for individuals with first-episode psychosis (FEP). Group teletherapy is both accessible and satisfactory to individuals with FEP. Group teletherapy has potential as a more standard and widespread treatment modality within coordinated specialty care for FEP.

Deprescribing anticholinergic medication in the community mental health setting: A quality improvement initiative.

BACKGROUND: Chronic anticholinergic medication (ACM) prescribing with antipsychotics when no longer clinically indicated can lead to serious side effects and adversely impact patient quality of life. OBJECTIVES: Through modifications of previously described deprescribing strategies undertaken in an academic, schizophrenia clinic, this quality improvement (QI) project aimed to bolster ACM deprescription where clinically appropriate among patients with schizophrenia and other psychiatric disorders at a community mental health center. METHODS: A multidisciplinary team involving clinical pharmacists and psychiatrists created web streaming video medical education accredited modules, supplemented by small groups sessions and case consultations, and provided these to psychiatrists and nurse practitioners at a community mental health center over a one-year period. Electronic medical record reports were also generated, highlighting patients who were receiving one of two ACM used in the clinic: benztropine and/or trihexyphenidyl; these were periodically distributed to support appropriate deprescription. Patient education infographic material focused on ACM were also created and deployed. RESULTS: One hundred and twenty-six patients were identified as receiving benztropine or trihexyphenidyl in March 2019. One hundred and six (84%) were on one or both of these medications for at least six months. The mean (±SD) age of the study sample was 53.4 (±12.6) years; a third of the sample was over 60 years. Thirty-seven patients, or 29.4%, had their ACM discontinued or the dosage reduced. Deprescription was not associated with age, sex, race, or diagnosis. Deprescription was not associated with antipsychotic polypharmacy, first versus second generation, or oral versus long acting preparation. CONCLUSIONS: These results suggest that deprescription of ACM in a community mental health center can occur with prescriber education and support. However, results from previous stages of this QI project, where much higher rates of deprescription were demonstrated, indicate the important benefit of more direct clinical pharmacist support and involvement in the process.

Racial Differences in S100b Levels in Persons with Schizophrenia.

The calcium-binding protein S100b is secreted by glial cells in the brain and is also expressed by melanocytes. In nanomolar concentrations, S100b is considered to be a neurotrophic factor, but in micromolar concentrations, it is thought to reflect CNS injury and inflammation. Seen as a potential biomarker in traumatic brain injury, meta-analytic data from several studies report that S100b levels are significantly higher in persons with long standing schizophrenia, but also among first-episode patients compared to healthy control subjects. However, ethnic or racial differences are typically not mentioned when reporting levels of S100b. We assessed serum S100b levels in persons with schizophrenia (n = 136) who were participants in two independent research studies using the same enzyme-linked immunoassay (ELISA). African-American subjects had significantly higher levels of S100b (41.9 pg/ml ± 62.2) than Caucasian subjects (24.9 pg/ml ± 45.4) in the combined dataset (Mann-Whitney U = 1307, p < 0.001), as well as in each independent study. There were no significant differences in S100b levels between men and women. No significant correlations were observed between S100b levels and demographic or clinical variables. These data suggest that ethnicity or race should be given serious consideration when studying and interpreting S100b levels in persons with schizophrenia.