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.

Antipsychotic drugs in first-episode psychosis: A target trial emulation in the FEP-CAUSAL Collaboration.

Good adherence to antipsychotic therapy helps prevent relapses in First Episode Psychosis (FEP). We used data from the FEP-CAUSAL Collaboration, an international consortium of observational cohorts to emulate a target trial comparing antipsychotics with treatment discontinuation as the primary outcome. Other outcomes included all-cause hospitalization. We benchmarked our results to estimates from EUFEST, a randomized trial conducted in the 2000s. We included 1097 patients with a psychotic disorder and less than 2 years since psychosis onset. Inverse probability weighting was used to control for confounding. The estimated 12-month risks of discontinuation for aripiprazole, first-generation agents, olanzapine, paliperidone, quetiapine, and risperidone (95% CI) were: 61.5% (52.5-70.6), 73.5% (60.5-84.9), 76.8% (67.2-85.3), 58.4% (40.4-77.4), 76.5% (62.1-88.5), and 74.4% (67.0-81.2) respectively. Compared with aripiprazole, the 12-month risk differences (95% CI) were -15.3% (-30.0, 0.0) for olanzapine, -12.8% (-25.7, -1.0) for risperidone, and 3.0% (-21.5, 30.8) for paliperidone. The 12-month risks of hospitalization were similar between agents. Our estimates support use of aripiprazole and paliperidone as first-line therapies for FEP. Benchmarking yielded similar results for discontinuation and absolute risks of hospitalization as in the original trial, suggesting that data from the FEP-CAUSAL Collaboration data sufficed to approximately remove confounding for these clinical questions.

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.

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.

Replication of a neuroimaging biomarker for striatal dysfunction in psychosis.

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.

Functional magnetic resonance imaging in schizophrenia: current evidence, methodological advances, limitations and future directions.

Functional neuroimaging emerged with great promise and has provided fundamental insights into the neurobiology of schizophrenia. However, it has faced challenges and criticisms, most notably a lack of clinical translation. This paper provides a comprehensive review and critical summary of the literature on functional neuroimaging, in particular functional magnetic resonance imaging (fMRI), in schizophrenia. We begin by reviewing research on fMRI biomarkers in schizophrenia and the clinical high risk phase through a historical lens, moving from case-control regional brain activation to global connectivity and advanced analytical approaches, and more recent machine learning algorithms to identify predictive neuroimaging features. Findings from fMRI studies of negative symptoms as well as of neurocognitive and social cognitive deficits are then reviewed. Functional neural markers of these symptoms and deficits may represent promising treatment targets in schizophrenia. Next, we summarize fMRI research related to antipsychotic medication, psychotherapy and psychosocial interventions, and neurostimulation, including treatment response and resistance, therapeutic mechanisms, and treatment targeting. We also review the utility of fMRI and data-driven approaches to dissect the heterogeneity of schizophrenia, moving beyond case-control comparisons, as well as methodological considerations and advances, including consortia and precision fMRI. Lastly, limitations and future directions of research in the field are discussed. Our comprehensive review suggests that, in order for fMRI to be clinically useful in the care of patients with schizophrenia, research should address potentially actionable clinical decisions that are routine in schizophrenia treatment, such as which antipsychotic should be prescribed or whether a given patient is likely to have persistent functional impairment. The potential clinical utility of fMRI is influenced by and must be weighed against cost and accessibility factors. Future evaluations of the utility of fMRI in prognostic and treatment response studies may consider including a health economics analysis.

COVID-19 Impacts on Pennsylvania Coordinated Specialty Care for Early Psychosis Participants.

OBJECTIVES: The coronavirus disease (COVID-19) pandemic produced swift, extensive changes in daily life, including for first-episode psychosis (FEP) clients. This study examined pandemic-related psychosocial impacts to clients while engaged in Coordinated Specialty Care (CSC). We also examined FEP client vaccination rates, as vaccinations can reduce hospitalizations/deaths, and related worries. METHODS: Thirty-one clients (45% female; ages 13-39; 26% black, 61% white) from Pennsylvania (PA) CSC outpatient programs completed an online survey evaluating exposure to COVID-19, associated worries, coping, and safety strategies. Descriptive statistics characterized responses and demographic group differences. Additional program evaluation data informed vaccination rates for PA FEP clients. RESULTS: Participants reported substantial pandemic-related impacts to daily life. Many clients reported improved safety measures to protect themselves/others from COVID-19. Clients largely denied substantial worries about infection for themselves, reporting greater concern for loved ones. Multiple coping strategies were endorsed, which, with few exceptions, did not differ among demographic groups. FEP clients had a low reported rate of vaccination (28.6%) as of September 2021. CONCLUSIONS: Observed prolonged pandemic effects may alter FEP client progress in CSC. Stakeholders should be prepared to adjust FEP treatment accordingly in the event of a similar disaster. Concentrated vaccination efforts may be necessary for this population.

Replication of a neuroimaging biomarker for striatal dysfunction in psychosis.

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 minutes, 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.

Replication of a neuroimaging biomarker for striatal dysfunction in psychosis.

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 minutes, 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.

Trauma and Trauma-Informed Care in Early Intervention in Psychosis: State of Implementation and Provider Views on Challenges.

OBJECTIVE: Although trauma is increasingly recognized as a major risk factor for psychosis and for its link to treatment outcomes, the landscape of trauma-related practices in specialized early psychosis services in the United States and other countries remains only poorly characterized. Research documenting the perspectives of frontline providers is also lacking. The primary goals of this study were to document the state of trauma-related policy implementation in early intervention in psychosis (EIP) programs and to gather provider perspectives. METHODS: This was a mixed-methods project involving an international EIP provider survey, followed by in-depth provider interviews. The survey was disseminated in Australia, Canada, Chile, the United Kingdom, and the United States. In total, 164 providers, representing 110 unique sites, completed the survey. Frequencies were calculated for responses to survey items, and open-ended responses were analyzed with a systematic content analysis. RESULTS: The survey findings suggested low implementation rates for a variety of assessment and support practices related to trauma and trauma-informed care. Coding of open-ended responses revealed numerous concerns and uncertainties among providers regarding the relationship between trauma and psychosis and the state of the EIP field. CONCLUSIONS: An expansion of research and service development aimed at better meeting the trauma-related needs of young people with psychosis is essential, with implications for EIP outcomes and service user and staff experiences.

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.

Tele-mental Health Transitions for Pennsylvania Coordinated Specialty Care Programs for Early Psychosis During the COVID-19 Pandemic.

This study examined provider and client perspectives of tele-mental health (TMH) in early psychosis care during the COVID-19 pandemic. To achieve this goal, thirty-three mental health providers and 31 clients from Pennsylvania Coordinated Specialty Care (CSC) programs completed web-based surveys assessing TMH usage, experiences, and perceptions between May and September 2020. Three additional TMH-related questions were asked two years later of PA CSC Program Directors between Feb and March 2022. Descriptive statistics characterized responses. Open-ended items were coded and grouped into themes for qualitative synthesis. As early as mid-2020, participants reported extensive use of TMH technologies, including telephone and video visits. Although most providers and clients preferred in-person care to TMH, most clients still found TMH to be comparable to or better than in-person care; 94% of clients indicated interest in future TMH services. Providers also noted more successes than challenges with TMH. Nine themes emerged regarding provider-perceived client characteristics that could benefit from TMH and were grouped into two categories: client-level (access to technology, comfort with technology, transportation, young age, symptom severity, functioning level, motivation for treatment adherence) and interpersonal-level (external support systems and engagement with program prior to the pandemic) characteristics. Two years later, program directors reported continued perceived advantages of TMH in CSCs, although some barriers persisted. Despite the unexpected shift to TMH in early psychosis programs during the COVID-19 pandemic, findings indicated a relatively positive transition to TMH and perceived promise of TMH as a sustained part of routine care.

Pathways Through Early Psychosis Care for U.S. Youths From Ethnically and Racially Minoritized Groups: A Systematic Review.

OBJECTIVE: The authors of this systematic review examined service utilization and outcomes among youths from ethnoracially minoritized groups after the youths initiated treatment for a psychotic disorder-that is, the youths' "pathway through care." Also examined were potential moderating variables in pathways through care for these youths at the clinic, family, and cultural levels. The goal was to describe methodologies, summarize relevant findings, highlight knowledge gaps, and propose future research on pathways through care for young persons from ethnoracially minoritized groups who experience early psychosis. METHODS: The PubMed, PsycInfo, and Web of Science literature databases were systematically searched for studies published between January 1, 2010, and June 1, 2021. Included articles were from the United States and focused on young people after they initiated treatment for early psychosis. Eighteen studies met inclusion criteria. RESULTS: Sixteen of the 18 studies were published in the past 5 years, and 11 had an explicit focus on race and ethnicity as defined by the studies' authors. Studies varied in terminology, outcomes measures, methodologies, and depth of analysis. Being an individual from an ethnoracially minoritized group appeared to affect care utilization and outcomes. Insufficient research was found about potential moderating variables at the clinic, family, and cultural levels. CONCLUSIONS: Studies of pathways through care for persons from minoritized groups warrant further funding and attention.

Dorsolateral Prefrontal Cortex Glutamate/Gamma-Aminobutyric Acid (GABA) Alterations in Clinical High Risk and First-Episode Schizophrenia: A Preliminary 7-T Magnetic Resonance Spectroscopy Imaging Study.

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.

A longitudinal investigation of GABA, glutamate, and glutamine across the insula during antipsychotic treatment of first-episode schizophrenia.

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 < 0.001), but no corresponding changes in Gln or GABA. In group analyses, the FES cohort showed lower levels of Glu (p < 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.

Subcortical brain iron deposition in individuals with schizophrenia.

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.

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.

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.

A narrative review of treatment interventions to improve cognitive performance in schizophrenia, with an emphasis on at-risk and early course stages.

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.