Over 30 years of STEP: The Pittsburgh experience with first-episode psychosis.

AIMS: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh. METHODS: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership. RESULTS: Research-based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic-based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi-state Learning Health System. STEP has retained a relatively unique 5-year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes. CONCLUSIONS: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments.

A quality improvement program for managing clozapine-induced constipation in a long-term structured residential setting for persons with serious mental illness.

OBJECTIVES: The goal of this quality improvement project (QIP) was to increase awareness of the serious medical consequences of clozapine-associated constipation to front line nursing staff and patients with schizophrenia. METHODS: The QIP was developed iteratively by psychiatric nurses, psychiatrists and pharmacists with input from patients. The processes involved a literature review, development of educational materials for staff and patients, and the creation of a daily bowel movements log (BML). Implementation involved review of the BML at treatment team meetings, and deployment of pharmacological and non-pharmacological interventions to resolve constipation and increase awareness and knowledge of this clinical concern. OUTCOMES: The initial pilot screened for symptoms of constipation in patients receiving clozapine and non-clozapine antipsychotic agents and intervening as necessary during multidisciplinary team meetings. Patients benefited from relief of constipation and improved bowel habits. Staff benefited from improved knowledge and making requisite changes in workflow and practice. Feedback allowed refinements to be made to the educational materials for patients and staff. Since full implementation, bowel habits are routinely monitored, and interventions are reviewed for effectiveness. Staff satisfaction with this QIP is reflected in answers to a structured questionnaire and in patient reports (n = 50). CONCLUSIONS: Clozapine, the only approved and efficacious medication for treatment-resistant schizophrenia is significantly underutilized. Medically consequential constipation can be a serious barrier to retention of patients benefiting from clozapine. Increased awareness and use of educational materials for patients and staff, routine monitoring of bowel habits combined with pharmacological and non-pharmacological interventions can successfully address this clinical problem.

Tobacco smoking and nicotine vaping in persons with first episode psychosis.

Tobacco smoking is highly prevalent in persons with psychosis and is the leading cause of preventable mortality in this population. Less is known about tobacco smoking in persons with first episode psychosis (FEP) and there have been no estimates about the prevalence of nicotine vaping in FEP. This study reports rates of tobacco smoking and nicotine vaping in young people with FEP enrolled in Coordinated Specialty Care programs in Pennsylvania and Maryland. Using data collected from 2021 to 2023, we examined lifetime and recent smoking and vaping and compared smokers and vapers to nonusers on symptoms, functioning, and substance use. The sample included 445 participants aged 13-35 with recent psychosis onset. Assessments were collected by program staff. Overall, 28 % of participants engaged in either smoking or vaping within 30 days of the admission assessment. Smokers and vapers were disproportionately male, cannabis users, and had lower negative symptom severity than non-smokers. Vapers had higher role and social functioning. Both smoking and vaping were related to a longer time from psychosis onset to program enrollment. We compare these findings to previous studies and suggest steps for addressing smoking and vaping in this vulnerable population.

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.

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.

Changes in corticostriatal connectivity and striatal tissue iron associated with efficacy of clozapine for treatment­resistant schizophrenia.

RATIONALE: Though numerous studies demonstrate the superiority of clozapine (CLZ) for treatment of persistent psychotic symptoms that are characteristic of treatment-refractory schizophrenia (TRS), what remains unknown are the neural and molecular mechanisms underlying CLZ's efficacy. Recent work implicates increased corticostriatal functional connectivity as a marker of response to non-CLZ, dopamine (DA) D2-receptor blocking antipsychotic drugs. However, it is undetermined whether this connectivity finding also relates to CLZ's unique efficacy, or if response to CLZ is associated with changes in striatal DA functioning. OBJECTIVE: In a cohort of 22 individuals with TRS, we examined response to CLZ in relation to the following: (1) change in corticostriatal functional connectivity; and (2) change in a magnetic resonance-based measure of striatal tissue iron (R2'), which demonstrates utility as a proxy measure for elements of DA functioning. METHODS: Participants underwent scanning while starting CLZ and after 12 weeks of CLZ treatment. We used both cortical and striatal regions of interest to examine changes in corticostriatal interactions and striatal R2' in relation to CLZ response (% reduction of psychotic symptoms). RESULTS: We first found that response to CLZ was associated with an increase in corticostriatal connectivity between the dorsal caudate and regions of the frontoparietal network (P < 0.05, corrected). Secondly, we observed no significant changes in striatal R2' across CLZ treatment. CONCLUSION: Overall, these results indicate that changes in corticostriatal networks without gross shifts in striatal DA functioning underlies CLZ response. Our results provide novel mechanistic insight into response to CLZ treatment.

Relationship between plasma clozapine/N-desmethylclozapine and changes in basal forebrain-dorsolateral prefrontal cortex coupling in treatment-resistant schizophrenia.

Clozapine (CLZ) demonstrates a unique clinical efficacy relative to other antipsychotic drugs. Previous work has linked the plasma ratio of CLZ and its major metabolite, N-desmethylclozapine (NDMC), to an inverse relationship with cognition via putative action on the cholinergic system. However, neuroimaging correlates of CLZ/NDMC remain unknown. Here, we examined changes in basal forebrain functional connectivity with the dorsolateral prefrontal cortex, and secondly, cognition in relation to the CLZ/NDMC ratio. A cohort of nineteen chronically ill participants with treatment-resistant schizophrenia (TRS) undergoing 12 weeks of CLZ treatment were included. Measures of cognition and plasma CLZ/NDMC ratios were obtained in addition to resting-state functional neuroimaging scans, captured at baseline and after 12 weeks of CLZ treatment. We observed a significant correlation between basal forebrain-DLPFC connectivity and CLZ/NDMC ratios across CLZ treatment (p = 0.02). Consistent with previous findings, we also demonstrate a positive relationship between CLZ/NDMC ratio and working memory (p = 0.03). These findings may reflect the action of CLZ and NDMC on the muscarinic cholinergic system, highlighting a possible neural correlate of cognition across treatment.

Treating Insulin Resistance With Metformin as a Strategy to Improve Clinical Outcomes in Treatment-Resistant Bipolar Depression (the TRIO-BD Study): A Randomized, Quadruple-Masked, Placebo-Controlled Clinical Trial.

Objective: Therapeutic options are limited for treatment-resistant bipolar depression (TRBD). Insulin resistance (IR) confers increased risk for TRBD. We investigated metformin, an insulin sensitizer, to reverse IR and improve clinical outcomes in TRBD.Methods: Using a random-assignment (1:1), intent-to-treat, 2-site, quadruple-masked, parallel-group (metformin to 2,000 mg/d or placebo) clinical trial design, patients with DSM-5 bipolar disorder (BD) type I or II and IR received study medication for 26 weeks (February 2016 to October 2019). The primary outcome was the change in depression rating scores (Montgomery-Asberg Depression Rating Scale [MADRS]) at 14 weeks between those who no longer met IR criteria (converters) and those who still did (non-converters). Additional outcomes included scores on the Global Assessment of Functioning (GAF); the Clinical Global Impressions Scale, Bipolar Disorders version (CGI-BP); and the Hamilton Anxiety Rating Scale (HAM-A) and maintenance of improved outcomes up to 26 weeks.Results: Forty-five BD patients were randomized to metformin (n = 20) or placebo (n = 25), and at 14 weeks or later, 11 subjects no longer met IR criteria (n = 10 with metformin, n = 1 with placebo; P = .0009). These converters experienced significant improvements in MADRS (P values ranged from .031 to .008) and GAF (P values ranged from .045 to .008) scores compared to non-converters beginning at week 6, sustained to week 26. HAM-A (P = .022 at week 14 and .019 at week 26) and CGI-BP change scores (P = .046 at 26 weeks) significantly favored converters over non-converters. Effect sizes were large for the MADRS and GAF (Cohen d > 1 at 14 and 26 weeks) and large for the HAM-A and CGI-BP at 26 weeks. Transient gastrointestinal side effects occurred under both treatment conditions.Conclusions: Pending replication, this early study suggests that reversal of IR by metformin offers a path out of TRBD. Further characterization of metformin converters with TRBD will prove informative.Trial Registration: ClinicalTrials.gov identifier: NCT02519543.

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.

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.

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.