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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., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.) more...

To bring biomarkers closer to clinical application, they should be generalizable, reliable, and maintain performance within the constraints of routine clinical conditions. The functional striatal abnormalities (FSA), is among the most advanced neuroimaging biomarkers in schizophrenia, trained to discriminate diagnosis, with post-hoc analyses indicating prognostic properties. Here, we attempt to replicate its diagnostic capabilities measured by the area under the curve (AUC) in receiver operator characteristic curves discriminating individuals with psychosis (n = 101) from healthy controls (n = 51) in the Human Connectome Project for Early Psychosis. We also measured the test-retest (run 1 vs 2) and phase encoding direction (i.e., AP vs PA) reliability with intraclass correlation coefficients (ICC). Additionally, we measured effects of scan length on classification accuracy (i.e., AUCs) and reliability (i.e., ICCs). Finally, we tested the prognostic capability of the FSA by the correlation between baseline scores and symptom improvement over 12 weeks of antipsychotic treatment in a separate cohort (n = 97). Similar analyses were conducted for the Yeo networks intrinsic connectivity as a reference. The FSA had good/excellent diagnostic discrimination (AUC = 75.4%, 95% CI = 67.0-83.3%; in non-affective psychosis AUC = 80.5%, 95% CI = 72.1-88.0%, and in affective psychosis AUC = 58.7%, 95% CI = 44.2-72.0%). Test-retest reliability ranged between ICC = 0.48 (95% CI = 0.35-0.59) and ICC = 0.22 (95% CI = 0.06-0.36), which was comparable to that of networks intrinsic connectivity. Phase encoding direction reliability for the FSA was ICC = 0.51 (95% CI = 0.42-0.59), generally lower than for networks intrinsic connectivity. By increasing scan length from 2 to 10 min, diagnostic classification of the FSA increased from AUC = 71.7% (95% CI = 63.1-80.3%) to 75.4% (95% CI = 67.0-83.3%) and phase encoding direction reliability from ICC = 0.29 (95% CI = 0.14-0.43) to ICC = 0.51 (95% CI = 0.42-0.59). FSA scores did not correlate with symptom improvement. These results reassure that the FSA is a generalizable diagnostic - but not prognostic - biomarker. Given the replicable results of the FSA as a diagnostic biomarker trained on case-control datasets, next the development of prognostic biomarkers should be on treatment-response data., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.) more...

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., Competing Interests: The authors report no financial relationships with commercial interests. more...

Converging lines of evidence suggest that an imbalance between excitation and inhibition is present in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia (SCZ). Gamma-aminobutyric-acid (GABA) and, to a lesser extent, glutamate (Glu) abnormalities were reported in the DLPFC of SCZ patients, especially on the right hemisphere, by post-mortem studies. However, in vivo evidence of GABA, Glu, and Glu/GABA DLPFC abnormalities, particularly on the right side and the early stages of illness, is limited. In this preliminary study, we utilized 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to investigate bilateral Glu/Creatine (Cre), GABA/Cre, and Glu/GABA in the DLPFC of sixteen first episode schizophrenia (FES), seventeen clinical high risk (CHR), and twenty-six healthy comparison (HC) subjects. FES and CHR had abnormal GABA/Cre and Glu/GABA in the right DLPFC (rDLPFC) compared with HC participants, while no differences were observed in the left DLPFC (lDLPFC) among the three groups. Furthermore, HC had higher Glu/GABA in rDLPFC compared to lDLPFC (R > L), whereas the opposite relationship (R < L) was observed in the DLPFC Glu/GABA of FES patients. Altogether, these findings indicate that GABA/Cre and Glu/GABA DLPFC alterations are present before illness manifestation and worsen in FES patients, thus representing a putative early pathophysiological biomarker for SCZ and related psychotic disorders. more...

Cognitive dysfunction is a core feature of schizophrenia (SCZ), which unfavorably affects SCZ patients' daily functioning and overall clinical outcome. An increasing body of evidence has shown that cognitive deficits are present not only at the beginning of the illness but also several years before the onset of psychosis. Nonetheless, the majority of treatment interventions targeting cognitive dysfunction in SCZ, using both pharmacological and nonpharmacological approaches, have focused on chronic patients rather than individuals at high risk or in the early stages of the disease. In this article, we provide a narrative review of cognitive interventions in SCZ patients, with a particular focus on pre-emptive interventions in at-risk/early course individuals when available. Furthermore, we discuss current challenges for these pre-emptive treatment interventions and provide some suggestions on how future work may ameliorate cognitive dysfunction in these individuals., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.) more...

Individuals with first-episode schizophrenia (FES) typically present with acute psychotic symptoms. Though antipsychotic drugs are the mainstay for treatment, the neurobiology underlying successful treatment remains largely elusive. Recent evidence from functional connectivity studies highlights the insula as a key structure in the neural mechanism of response. However, molecular contributions to response across insular regions remain largely unknown. We used 7-Tesla magnetic resonance spectroscopic imaging (MRSI) to measure glutamate (Glu), Glutamine (Gln), and GABA from anterior and posterior regions of the insula across antipsychotic treatment. A total of 36 participants were examined, including 15 individuals with FES and moderate to severe psychosis who were scanned at two time points, while starting and after 6 weeks of antipsychotic treatment. Symptoms were carefully monitored across the study period to characterize treatment response. GABA, Glu, and Gln levels were calculated relative to creatine in anterior and posterior insular regions, bilaterally. In relation to psychotic symptom reduction, we observed a significant increase in Glu across all insular regions with (p &lt; 0.001), but no corresponding changes in Gln or GABA. In group analyses, the FES cohort showed lower levels of Glu (p &lt; 0.001) and GABA (p = 0.02) at baseline. Finally, in exploratory analyses, treatment remitters demonstrated a normalization of lower insular Glu levels across treatment, unlike non-remitters. Overall, these findings contribute to our understating of molecular changes associated with antipsychotic response and demonstrate abnormalities specific to the insula in FES., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.) more...

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., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.) more...

Subcortical structures play a critical role the pathophysiology and treatment of schizophrenia (SZ), yet underlying neurophysiological processes, in vivo, remain largely unexplored. Brain tissue iron, which can be measured with magnetic resonance-based methods, is a crucial component of a variety of neuronal functions including neurotransmitter synthesis. Here we used a proxy measure of tissue iron to examine basal ganglia and thalamic structures in an adult cohort of individuals with chronic SZ. A publicly available dataset of 72 individuals with SZ between ages 18 and 65, and a matched sample of 74 healthy control (HC) participants were included. A novel method that calculated the inverse-normalized T2*-weighted contrast (1/nT2*) was used to estimate brain iron within the basal ganglia and thalamus. Between group, age- and sex-related differences in 1/nT2* were examined, in addition to correlations with measures of psychopathology and cognition. Individuals with SZ showed greater 1/nT2* (iron index) compared to HCs in the thalamus (p < 0.01, FWE corrected). Age-related 1/nT2* accumulation was noted in regions of the basal ganglia, coinciding with prior work, and prominent sex-differences were noted in the caudate and thalamus (p < 0.01, FWE corrected). No significant relationship was observed between 1/nT2* and measures of neurocognition or psychopathology. Overall, our findings characterize a non-invasive proxy measure of tissue iron in SZ and highlight thalamic iron accumulation as a potential marker of illness., (Copyright © 2022 Elsevier Ltd. All rights reserved.) more...

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., (Copyright © 2022 Elsevier B.V. All rights reserved.) more...

Aim: Pennsylvania (PA) first-episode psychosis (FEP) program evaluation is a statewide initiative, supported by the PA Office of Mental Health and Substance Abuse Services (PA-OMHSAS) and administered by PA Early Intervention Center/Heads Up, which evaluates fidelity and outcomes of PA Coordinated Specialty Care (CSC) programs. Programs participate in standard computerized measures of CSC outcomes using centralized informatics. The aims of the current report are to describe implementation of this core battery for program evaluation in PA and to present 6- and 12-month outcomes., Methods: Participants (n = 697) from nine PA CSC programs completed the core battery at admission. The battery was re-administered at 6- and 12-month follow-up, and data were analysed for individuals (n = 230) who had completed 12-months of treatment. Domains assessed via clinician report and/or self-report included symptoms, role and social functioning, self-perceived recovery and service utilization., Results: PA FEP CSC participants showed improvement over time in several domains, including decreased symptoms, higher role and social functioning, decreased hospitalizations, and improved self-perception of recovery, quality of life, and services satisfaction. Trends towards improvements were observed for participant happiness, hopelessness, and school-enrolment. Nearly all improvements were observed at 6-month follow-up, with earlier gains maintained at 12-months., Conclusions: PA FEP CSC programs demonstrate the ability to assess and improve critical outcomes of coordinated specialty care in PA. Improved outcomes by 12 months in treatment provides evidence of an effective treatment model and supports the continuation of these programs in pursuit of our goal of reducing schizophrenia disease burden on individuals and society., (© 2020 John Wiley & Sons Australia, Ltd.) more...

Background: Abnormalities between the prefrontal cortex and basal ganglia have been described by numerous studies of schizophrenia (SZ). We recently reported that individuals with first episode SZ who develop greater vocational and social impairments show lower baseline functional connectivity between the globus pallidus (GP) and regions of the intrinsic salience network. Here we extend these findings to probe the integrity of this system in individuals with chronic illness., Methods: All data were obtained from a publicly available Center of Biomedical Research Excellence dataset (http://fcon&#95;1000., Projects: nitric.org/indi/retro/cobre.html) that included resting-state fMRI and structural scans, and an array of clinical and neuropsychological measures. Participants with SZ were divided into high- or low-functioning groups based on scores across measures of psychopathology and cognitive functioning. Corticopallidal functional connectivity was examined between low- and high-functioning individuals with SZ and matched healthy control participants. We focused on connectivity between GP structures and a priori regions of the salience network that were significant in our previous study. Exploratory voxel-wise analyses were also conducted., Results: Lower functioning individuals with SZ demonstrated less connectivity between bilateral GP externa and nodes within the salience network, relative to healthy controls. No connectivity differences were observed between low- and high-functioning individuals with SZ. Exploratory voxel-wise analyses highlighted additional large-scale corticopallidal abnormalities in lower-functioning participants with SZ., Conclusions: These results confirm our previous work in a more chronic cohort of individuals with SZ. Our findings further advance corticopallidal connectivity as a biomarker of functional impairments in SZ and lay the groundwork for treatment-based studies., (Copyright © 2019 Elsevier B.V. All rights reserved.) more...

There is growing evidence suggesting that abnormalities in cortical-basal ganglia circuitry may play a significant role in determining outcomes in schizophrenia. The globus pallidus (GP), a critical structure within this circuitry, unique in its role as a mediator of competing inputs through the striatum, has not been well characterized in schizophrenia. The following study examined functional interactions of the GP in individuals with first-episode schizophrenia (FES). To probe the large-scale intrinsic connectivity of the GP, resting-state fMRI scans were obtained from patients with FES and sex and age-matched healthy controls. Participants with FES were also evaluated after 6 months via the Strauss-Carpenter Outcomes Scale to assess overall functional trajectory. The GP was parcellated to generate seeds within its substructures, and connectivity maps were generated. Our FES cohort showed significantly lower functional connectivity between the left GP interna and a network of regions including the dorsolateral prefrontal cortex, caudate, and cerebellum at baseline. In addition, FES participants with lower overall scores of functioning at 6 months showed significantly decreased connectivity between the GP interna and the dorsal anterior cingulate and bilateral insula, all regions important for motivational salience. These results provide novel evidence for unique abnormalities in functional interactions of the GP with key prefrontal cortical regions in FES. Our findings also suggest that reduced prefrontal-pallidal connectivity may serve as a predictor of early functional outcome., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.) more...

Antipsychotic drugs are the primary treatment for psychosis, yet individual response to their administration remains variable. At present, no biological predictors of response exist to guide clinicians as they select treatments for patients, and our understanding of the neurobiology underlying the heterogeneity of outcomes remains limited. Magnetic Resonance Imaging (MRI) has been applied by numerous studies to examine the response to antipsychotic treatment, though a large gap remains between their results and our clinical practice. To advance patient care with precision medicine approaches, prior work must be accounted for and built upon with future studies. This review provides an overview of studies that relate treatment outcome to various MRI-related measures, including structural, spectroscopic, diffusion tensor, and functional imaging. Knowledge derived from these studies will be discussed along with future directions for the field., (Copyright © 2018 Elsevier Inc. All rights reserved.) more...

Patients with first-episode psychosis experience psychotic symptoms for a mean of up to 2 years prior to initiation of treatment, and long duration of untreated psychosis (DUP) is associated with poor clinical outcomes. Meanwhile, evidence compiled from numerous studies suggests that longer DUP is not associated with structural brain abnormalities. To date, few studies have examined the relationship between DUP and functional neuroimaging measures. In the present study, we used seed-based resting-state functional connectivity to examine the impact of DUP on corticostriatal circuitry. We included 83 patients with early phase schizophrenia and minimal exposure to antipsychotic drugs (<2 years), who underwent resting state scanning while entering 12 weeks of prospective treatment with second-generation antipsychotic drugs. Functional connectivity maps of the striatum were generated and examined in relation to DUP as a covariate. Mediation analyses were performed on a composite measure of corticostriatal connectivity derived from the significant results of our DUP analysis. We found that longer DUP correlated with worse response to treatment as well as overall decreased functional connectivity between striatal nodes and specific regions within frontal and parietal cortices. Moreover, the relationship between DUP and treatment response was significantly mediated by corticostriatal connectivity. Our results indicate that variation in corticostriatal circuitry may play a role in the relationship between longer DUP and worsened response to treatment. Future prospective studies are necessary to further characterize potential causal links between DUP, striatal circuitry and clinical outcomes. more...

Objective: Clinical response to antipsychotic drug treatment is highly variable, yet prognostic biomarkers are lacking. The authors recently demonstrated that successful antipsychotic drug treatment alters resting-state functional connectivity of the striatum. The goal of the present study was to test whether intrinsic striatal connectivity patterns provide prognostic information and can serve as a potential biomarker of treatment response to antipsychotic drugs., Method: The authors used resting-state functional MRI (fMRI) to develop a prognostic index in a discovery cohort of 41 first-episode schizophrenia patients, then tested this index in an independent cohort of 40 newly hospitalized chronic patients with acute psychosis. In the discovery cohort, patients underwent resting-state fMRI scanning at the initiation of randomized controlled treatment with a second-generation antipsychotic. Whole-brain functional connectivity maps were generated for each subject from striatal seed regions. A stringent measure of clinical response was calculated that required sustained improvement over two consecutive study visits. Clinical response was entered into a survival analysis, and Cox regression was applied to the functional connectivity data. A striatal connectivity index was created, comprising functional connections of the striatum that predicted treatment response. This striatal connectivity index was tested on a generalizability cohort of patients with psychotic disorders who were hospitalized for an acute psychotic episode., Results: A total of 91 regions functionally connected with the striatum provided significant prognostic information. Connectivity in these regions was used to create a baseline striatal connectivity index that predicted response to antipsychotic treatment with high sensitivity and specificity in both the discovery and generalizability cohorts., Conclusions: These results provide evidence that individual differences in striatal functional connectivity predict response to antipsychotic drug treatment in acutely psychotic patients. With further development, this has the potential to serve as a prognostic biomarker with clinical utility and to reduce the overall burden associated with psychotic illnesses. more...

Importance: Previous evidence has implicated corticostriatal abnormalities in the pathophysiology of psychosis. Although the striatum is the primary target of all efficacious antipsychotics, the relationship between its functional connectivity and symptomatic reduction remains unknown., Objective: To explore the longitudinal effect of treatment with second-generation antipsychotics on functional connectivity of the striatum during the resting state in patients experiencing a first episode of psychosis., Design, Setting, and Participants: This prospective controlled study took place at a clinical research center and included 24 patients with first-episode psychosis and 24 healthy participants matched for age, sex, education, and handedness. Medications were administered in a double-blind randomized manner., Interventions: Patients were scanned at baseline and after 12 weeks of treatment with either risperidone or aripiprazole. Their symptoms were evaluated with the Brief Psychiatric Rating Scale at baseline and follow-up. Healthy participants were scanned twice within a 12-week interval., Main Outcomes and Measures: Functional connectivity of striatal regions was examined via functional magnetic resonance imaging using a seed-based approach. Changes in functional connectivity of these seeds were compared with reductions in ratings of psychotic symptoms., Results: Patients had a median exposure of 1 day to antipsychotic medication prior to being scanned (mean [SD] = 4.5 [6.1]). Eleven patients were treated with aripiprazole and 13 patients were treated with risperidone. As psychosis improved, we observed an increase in functional connectivity between striatal seed regions and the anterior cingulate, dorsolateral prefrontal cortex, and limbic regions such as the hippocampus and anterior insula (P < .05, corrected for multiple comparisons). Conversely, a negative relationship was observed between reduction in psychosis and functional connectivity of striatal regions with structures within the parietal lobe (P < .05, corrected for multiple comparisons)., Conclusions and Relevance: Our results indicated that corticostriatal functional dysconnectivity in psychosis is a state-dependent phenomenon. Increased functional connectivity of the striatum with prefrontal and limbic regions may be a biomarker for improvement in symptoms associated with antipsychotic treatment. more...