Implementation Barriers and Experiences of Eligible Patients Who Failed to Enroll in Collaborative Care for Depression and Anxiety.

BACKGROUND: Effective and efficient implementation of the Collaborative Care Model (CoCM) for depression and anxiety is imperative for program success. Studies examining barriers to implementation often omit patient perspectives. OBJECTIVES: To explore experiences and attitudes of eligible patients referred to CoCM who declined participation or were unable to be reached, and identify implementation barriers to inform strategies. DESIGN: Convergent mixed-methods study with a survey and interview. PARTICIPANTS: Primary care patients at an academic medical center who were referred to a CoCM program for anxiety and depression by their primary care clinician (PCC) but declined participation or were unable to be reached by the behavioral health care manager to initiate care (n = 80). Interviews were conducted with 45 survey respondents. MAIN MEASURES: Survey of patients' referral experiences and behavioral health preferences as they related to failing to enroll in the program. Interview questions were developed using the Consolidated Framework for Implementation Research version 2.0 (CFIR 2.0) to identify implementation barriers to enrollment. KEY RESULTS: Survey results found that patients were uncertain about insurance coverage, did not understand the program, and felt services were not necessary. Referred patients who declined participation were concerned about how their mental health information would be used and preferred treatment without medication. Men agreed more that they did not need services. Qualitative results exhibited a variety of implementation determinants (n = 23) across the five CFIR 2.0 domains. Barriers included mental health stigma, perceiving behavioral health as outside of primary care practice guidelines, short or infrequent primary care appointments, prioritizing physical health over mental health, receiving inaccurate program information, low motivation to engage, and a less established relationship with their PCC. CONCLUSIONS: Multiple barriers to enrollment led to failing to link patients to care, which can inform implementation strategies to address the patient-reported experiences and concerns.

Postoperative but not preoperative depression is associated with cognitive impairment after cardiac surgery: exploratory analysis of data from a randomized trial.

BACKGROUND: In this study we hypothesize that depression is associated with perioperative neurocognitive dysfunction and altered quality of life one month after surgery. METHODS: Data were obtained as part of a study evaluating cerebral autoregulation monitoring for targeting arterial pressure during cardiopulmonary bypass. Neuropsychological testing was performed before surgery and one month postoperatively. Testing included the Beck Depression Inventory, a depression symptoms questionnaire (0-63 scale), as well as anxiety and quality of life assessments. Depression was defined as a Beck Depression Inventory score > 13. RESULTS: Beck Depression data were available from 320 patients of whom cognitive domain endpoints were available from 88-98% at baseline and 69-79% after surgery. This range in end-points data was due to variability in the availability of each neuropsychological test results between patients. Depression was present in 50 (15.6%) patients before surgery and in 43 (13.4%) after surgery. Baseline depression was not associated with postoperative domain-specific neurocognitive function compared with non-depressed patients. Those with depression one month after surgery, though, had poorer performance on tests of attention (p = 0.017), memory (p = 0.049), verbal fluency (p = 0.010), processing speed (p = 0.017), and fine motor speed (p = 0.014). Postoperative neurocognitive dysfunction as a composite outcome occurred in 33.3% versus 14.5% of patients with and without postoperative depression (p = 0.040). Baseline depression was associated with higher anxiety and lower self-ratings on several quality of life domains, these measures were generally more adversely affected by depression one month after surgery. CONCLUSIONS: The results of this exploratory analysis suggests that preoperative depression is not associated with perioperative neurocognitive dysfunction, but depression after cardiac surgery may be associated with impairment in in several cognitive domains, a higher frequency of the composite neurocognitive outcome, and altered quality of life. TRIAL REGISTRATION: www. CLINICALTRIALS: gov, NCT00981474 (parent study).

Thalamic Shape Abnormalities Differentially Relate to Cognitive Performance in Early-Onset and Adult-Onset Schizophrenia.

Early-onset schizophrenia (EOS) shares many biological and clinical features with adult-onset schizophrenia (AOS), but may represent a unique subgroup with greater susceptibility for disease onset and worsened symptomatology and progression, which could potentially derive from exaggerated neurodevelopmental abnormalities. Neurobiological explanations of schizophrenia have emphasized the involvement of deep-brain structures, particularly alterations of the thalamus, which have been linked to core features of the disorder. The aim of this study was to compare thalamic shape abnormalities between EOS and AOS subjects and determine whether unique behavioral profiles related to these differences. It was hypothesized abnormal thalamic shape would be observed in anterior, mediodorsal and pulvinar regions in both schizophrenia groups relative to control subjects, but exacerbated in EOS. Magnetic resonance T1-weighted images were collected from adult individuals with EOS (n = 28), AOS (n = 33), and healthy control subjects (n = 60), as well as collection of clinical and cognitive measures. Large deformation high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. General linear models were used to compare groups on surface shape features, and Pearson correlations were used to examine relationships between thalamic shape and behavioral measures. Results revealed both EOS and AOS groups demonstrated significant abnormal shape of anterior, lateral and pulvinar thalamic regions relative to CON (all p < 0.007). Relative to AOS, EOS exhibited exacerbated abnormalities in posterior lateral, mediodorsal and lateral geniculate thalamic regions (p = 0.003). Thalamic abnormalities related to worse episodic memory in EOS (p = 0.03) and worse working memory (p = 0.047) and executive functioning (p = 0003) in AOS. Overall, findings suggest thalamic abnormalities are a prominent feature in both early- and late-onset schizophrenia, but exaggerated in EOS and have different brain-behavior profiles for each. The persistence of these abnormalities in adult EOS patients suggests they may represent markers of disrupted neurodevelopment that uniquely relate to the clinical and cognitive aspects of the illness.

Shape features of working memory-related deep-brain regions differentiate high and low community functioning in schizophrenia.

We have previously shown that schizophrenia (SCZ) participants with high community functioning demonstrate better verbal working memory (vWM) performance relative to those with low community functioning. In the present study, we investigated whether neuroanatomical differences in regions supporting vWM also exist between schizophrenia groups that vary on community functioning. Utilizing magnetic resonance imaging, shape features of deep-brain nuclei known to be involved in vWM were calculated in samples of high functioning (HF-SCZ, n = 23) and low functioning schizophrenia participants (LF-SCZ, n = 18), as well as in a group of healthy control participants (CON, n = 45). Large deformation diffeomorphic metric mapping was employed to characterize surface anatomy of the caudate nucleus, globus pallidus, hippocampus, and thalamus. Statistical analyses involved linear mixed-effects models and vertex-wise contrast mapping to assess between-group differences in structural shape features, and Pearson correlations to evaluate relationships between shape metrics and vWM performance. We found significant between-group main effects in deep-brain surface anatomy across all structures. Post-hoc comparisons revealed HF-SCZ and LF-SCZ groups significantly differed on both caudate and hippocampal shape, however, significant correlations with vWM were only observed in hippocampal shape for both SCZ groups. Specifically, more abnormal hippocampal deformation was associated with lower vWM suggesting hippocampal shape is both a neural substrate for vWM deficits and a potential biomarker to predict or monitor the efficacy of cognitive rehabilitation. These findings add to a growing body of literature related to functional outcomes in schizophrenia by demonstrating unique shape patterns across the spectrum of community functioning in SCZ.

PANSS Individual Item and Marder Dimension Analyses From a Pivotal Trial of RBP-7000 (Monthly Extended-Release Risperidone) in Schizophrenia Patients.

Background: Positive and Negative Syndrome Scale (PANSS) data from a pivotal phase 3 study in participants with schizophrenia of RBP-7000, a recently marketed long-acting subcutaneous injectable risperidone formulation, were examined to determine if dose-response relationships existed for different items of the PANSS.Methods: Changes in the 30 PANSS items were analyzed individually and using the 5 factor-analysis-derived dimensions defined by Marder and colleagues. Subgroups of patients who could benefit from the RBP-7000 120 mg dose were investigated.Results: 337 participants were randomized and received study medication (RBP-7000 90 mg n = 111, RBP-7000 120 mg n = 114, placebo n = 112). Dose-dependent responses were observed in items from the study-specified PANSS positive and general psychopathology exploratory subscales. Dose-dependent responses were observed across all 5 Marder dimensions, with the largest effect sizes observed with the 120 mg dose in the uncontrolled hostility/excitement (UHE) and anxiety/depression dimensions. Participants with baseline UHE dimension scores ≥ 9 demonstrated greater improvement in PANSS total score at the 120 mg dose compared to the 90 mg dose.Conclusions: RBP-7000 demonstrated efficacy across both the primary and exploratory PANSS study endpoints and the post hoc Marder dimensions. Schizophrenia patients with higher baseline Marder UHE scores may benefit from initiation of treatment at the 120 mg dose.Trial Registration: ClinicalTrials.gov identifier: NCT02109562.

Collaborative care for depression management in primary care: A randomized roll-out trial using a type 2 hybrid effectiveness-implementation design.

BACKGROUND: The Collaborative Care Model (CoCM) is a well-established treatment for depression in primary care settings. The critical drivers and specific strategies for improving implementation and sustainment are largely unknown. Rigorous pragmatic research is needed to understand CoCM implementation processes and outcomes. METHODS: This study is a hybrid Type 2 randomized roll-out effectiveness-implementation trial of CoCM in 11 primary care practices affiliated with an academic medical center. The Collaborative Behavioral Health Program (CBHP) was developed as a means of improving access to effective mental health services for depression. Implementation strategies are provided to all practices. Using a sequential mixed methods approach, we will assess key stakeholders' perspectives on barriers and facilitators of implementation and sustainability of CBHP. The speed and quantity of implementation activities completed over a 30-month period for each practice will be assessed. Economic analyses will be conducted to determine the budget impact and cost offset of CBHP in the healthcare system. We hypothesize that CBHP will be effective in reducing depressive symptoms and spillover effects on chronic health conditions. We will also examine differential outcomes among racial/ethnic minority patients. DISCUSSION: This study will elucidate critical drivers of successful CoCM implementation. It will be among the first to conduct economic analyses on a fee-for-service model utilizing billing codes for CoCM. Data may inform ways to improve implementation efficiency with an optimization approach to successive practices due to the roll-out design. Changes to the protocol and current status of the study are discussed.

Basal ganglia shape features differentiate schizoaffective disorder from schizophrenia.

There is growing evidence that schizophrenia and schizoaffective disorder represent closely related syndromes that vary in severity along a neurobiological continuum. In the present study, volume and shape of the basal ganglia was examined in people with schizophrenia and schizoaffective disorder relative to healthy controls and hypothesized that unique neuroanatomical differences would be observed in each patient group. Magnetic resonance 1.5T images were obtained from schizophrenia (n = 47), schizoaffective disorder (n = 15), and from healthy control (n = 42) participants, matched for age, gender, parental socioeconomic status, and race. The caudate, putamen, and globus pallidus were characterized using high-dimensional brain mapping procedures (Csernansky et al., 2004b). Results revealed significant shape deformations between schizophrenia and schizoaffective disorder that also differed from control subjects. Relative to schizophrenia, schizoaffective subjects showed exaggerated inward deformations indicative of localized volume loss in subregions of the caudate, putamen, and globus pallidus (all p < 0.001). These shape features correlated with mental flexibility and negative symptoms in schizophrenia (all p < 0.05), but not schizoaffective disorder. To the extent that differences in important basal ganglia substructures reflect biological heterogeneity among these two psychotic illnesses, this data could prove useful in improving diagnostic precision, as well as informing the affective component of mental illness.

Cognitive Empathy and Longitudinal Changes in Temporo-Parietal Junction Thickness in Schizophrenia.

Objective: Deficits in cognitive empathy are well-documented in individuals with schizophrenia and are related to reduced community functioning. The temporoparietal junction (TPJ) is closely linked to cognitive empathy. We compared the relationship between baseline cognitive empathy and changes in TPJ thickness over 24 months between individuals with schizophrenia and healthy controls. Methods: Individuals with schizophrenia (n = 29) and healthy controls (n = 26) completed a cognitive empathy task and underwent structural neuroimaging at baseline and approximately 24 months later. Symmetrized percent change scores were calculated for right and left TPJ, as well as whole-brain volume, and compared between groups. Task accuracy was examined as a predictor of percent change in TPJ thickness and whole-brain volume in each group. Results: Individuals with schizophrenia demonstrated poorer accuracy on the cognitive empathy task (p < 0.001) and thinner TPJ cortex relative to controls at both time points (p = 0.01). In schizophrenia, greater task accuracy was uniquely related to less thinning of the TPJ over time (p = 0.02); task accuracy did not explain changes in left TPJ or whole-brain volume. Among controls, task accuracy did not explain changes in right or left TPJ, or whole-brain volume. Conclusions: Our findings suggest that greater cognitive empathy may explain sustained integrity of the right TPJ in individuals with schizophrenia, suggesting a contributory substrate for the long-term maintenance of this process in psychosis. Cognitive empathy was not related to changes in whole-brain volume, demonstrating the unique role of the TPJ in cognitive empathy.

Brain morphometric differences in youth with and without perinatally-acquired HIV: A cross-sectional study.

Youth with perinatally-acquired HIV (PHIV) experience specific and global cognitive deficits at increased rates compared to typically-developing HIV-uninfected youth. In youth with PHIV, HIV infects the brain early in development. Neuroimaging studies have demonstrated altered grey matter morphometry in youth with PHIV compared to typically-developing youth. This study examined cortical thickness, surface area, and gyrification of grey matter in youth (age 11-20 years old) with PHIV (n = 40) from the Pediatric HIV/AIDS Cohort Study (PHACS) compared to typically-developing presumed HIV uninfected and unexposed youth (n = 80) from the Pediatric Imaging, Neurocognition and Genetics Study (PING) using structural magnetic resonance imaging. This study also examined the relationship between grey matter morphometry and age. Youth with PHIV had reduced cortical thickness, surface area, and gyrification compared to typically-developing youth. In addition, an inverse relationship between age and grey matter volume was found in typically-developing youth, but was not observed in youth with PHIV. Longitudinal studies are necessary to understand the neurodevelopmental trajectory of youth with PHIV.

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests.

Improving the Evaluation of Adult Mental Disorders in the Criminal Justice System With Computerized Adaptive Testing.

OBJECTIVE: The authors sought to develop and validate a suite of dimensional measures of psychiatric syndromes for use in a criminal justice population. METHODS: The previously validated Computerized Adaptive Test-Mental Health (CAT-MH) was administered to a sample of 475 defendants in the Cook County Bond Court. Item-level data were used to determine which test items exhibited differential item functioning in this population compared with the population used for the original calibration. RESULTS: After removal of nine items that exhibited differential item functioning from the CAT-MH, correlations between scores based on the original calibration from a nonjustice-involved population and the newly computed scores based on a sample of bond court defendants showed a correlation coefficient of r=0.96 to r=0.99. CONCLUSIONS: With a slight modification of the original CAT-MH, the tool was successfully used to measure severity of depression, anxiety, mania and/or hypomania, suicidality, and substance use disorder in an English- and Spanish-speaking criminal justice population.

Monthly Extended-Release Risperidone (RBP-7000) in the Treatment of Schizophrenia: Results From the Phase 3 Program.

PURPOSE/BACKGROUND: The Phase 3 program for RBP-7000, a once-monthly subcutaneous (SC) extended-release risperidone formulation approved for treatment of schizophrenia, consisted of a double-blind placebo-controlled trial (previously reported) and a 52-week open-label study of monthly RBP-7000 120 mg. The primary objective of the open-label study was to evaluate the long-term safety and tolerability of RBP-7000 in adults with schizophrenia. A secondary objective was to assess long-term maintenance of effectiveness. METHODS/PROCEDURES: The 52-week Phase 3 open-label study (NCT02203838) enrolled 92 rollover participants from the double-blind trial (NCT02109562) and 408 stable (Positive and Negative Syndrome Scale [PANSS] total score, ≤70) de novo participants. Participants received up to 13 monthly SC injections of RBP-7000 120 mg. Safety assessments included treatment-emergent adverse events, injection-site assessments, vital signs, laboratory and ECG parameters, extrapyramidal symptoms, and suicidality. Clinical outcomes included the PANSS and Clinical Global Impression-Severity. FINDINGS/RESULTS: Overall, 367 participants (73.4%) reported 1 or more treatment-emergent adverse event; the most common were injection-site pain (13.0%) and weight increase (12.8%). Most participants (>80%) experienced no injection-site reactions. No clinically meaningful changes were observed in laboratory or electrocardiogram values, vital signs, extrapyramidal symptoms, or suicidality. Over 12 months of exposure, mean PANSS scores continued to improve in rollover participants and remained stable among de novo participants. Mean Clinical Global Impression-Severity scores remained stable among all participants. IMPLICATIONS/CONCLUSIONS: Except for anticipated injection-site reactions, RBP-7000 demonstrated a favorable safety and tolerability profile similar to oral risperidone. Notably, PANSS scores continued to improve for participants from the pivotal study and remained stable for de novo participants.

CNTNAP2 stabilizes interneuron dendritic arbors through CASK.

Contactin associated protein-like 2 (CNTNAP2) has emerged as a prominent susceptibility gene implicated in multiple complex neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability (ID), and schizophrenia (SCZ). The presence of seizure comorbidity in many of these cases, as well as inhibitory neuron dysfunction in Cntnap2 knockout (KO) mice, suggests CNTNAP2 may be crucial for proper inhibitory network function. However, underlying cellular mechanisms are unclear. Here we show that cultured Cntnap2 KO mouse neurons exhibit an inhibitory neuron-specific simplification of the dendritic tree. These alterations can be replicated by acute knockdown of CNTNAP2 in mature wild-type (WT) neurons and are caused by faulty dendrite stabilization rather than outgrowth. Using structured illumination microscopy (SIM) and stimulated-emission depletion microscopy (STED), two super-resolution imaging techniques, we uncovered relationships between nanoscale CNTNAP2 protein localization and dendrite arborization patterns. Employing yeast two-hybrid screening, biochemical analysis, in situ proximity ligation assay (PLA), SIM, and phenotype rescue, we show that these effects are mediated at the membrane by the interaction of CNTNAP2's C-terminus with calcium/calmodulin-dependent serine protein kinase (CASK), another ASD/ID risk gene. Finally, we show that adult Cntnap2 KO mice have reduced interneuron dendritic length and branching in particular cortical regions, as well as decreased CASK levels in the cortical membrane fraction. Taken together, our data reveal an interneuron-specific mechanism for dendrite stabilization that may provide a cellular mechanism for inhibitory circuit dysfunction in CNTNAP2-related disorders.

Corticotrophin releasing factor receptor 1 antagonists prevent chronic stress-induced behavioral changes and synapse loss in aged rats.

Mounting evidence suggests that chronic stress can alter brain structure and function and promote the development of neuropsychiatric disorders, such as depression and Alzheimer's disease. Although the results of several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown whether antagonists of a key stress regulator, the corticotrophin releasing factor receptor 1 (CRF1), can prevent stress-induced anxiety and memory deficits in animal models. In this study, we evaluated the potential benefits of two CRF1 antagonists, R121919 and antalarmin, for preventing stress-induced anxiety-related behavioral and memory deficits and neurodegeneration in aged rats. We stressed rats using isolation-restraint for 3 months starting from the 18 months of age. Subsets of animals were administrated either R121919 or antalarmin through food chow for 3 months, followed by a series of behavioral, biochemical and morphological analyses. We found that stressed aged rats displayed body weight losses and increased corticosterone levels, as well as anxiety-related behaviors and memory deficits. Additionally, chronic stress induced a loss of cortical dendritic spines and synapses. However, R121919 and antalarmin both prevented stress-induced behavioral changes including anxiety-related behaviors and memory deficits and prevented synapse loss, perhaps through reversing HPA axis dysfunction. These results suggest that CRF1 antagonists may hold promise as a potential therapy for preventing stress-induced anxiety and memory deficits in aged individuals.

Neural correlates of preserved facial affect perception in high functioning schizophrenia.

Individuals with 'high functioning' schizophrenia (HF-SCZ) may have preserved facial affect perception (FAP) compared to individuals with 'low functioning' schizophrenia (LF-SCZ). The neural mechanisms supporting preserved FAP in HF-SCZ have yet to be evaluated. This study compared brain activation during FAP performance in HF-SCZ, LF-SCZ, and controls. Results demonstrated greater activation in the precuneus in CON compared to both SCZ groups, while HF-SCZ activated this region intermediate to controls and LF-SCZ. These preliminary findings suggest greater precuneus activation may be related to preserved FAP in HF-SCZ compared to LF-SCZ, though future research is needed to further evaluate differences between groups.

Δ9-tetrahydrocannabinol (Δ9-THC) administration after neonatal exposure to phencyclidine potentiates schizophrenia-related behavioral phenotypes in mice.

The clinical onset of schizophrenia often coincides with cannabis use in adolescents and young adults. However, the neurobiological consequences of this co-morbidity are not well understood. In this study, we examined the effects of Δ9-THC exposure during early adulthood on schizophrenia-related behaviors using a developmental mouse model of schizophrenia. Phencyclidine (PCP) or saline was administered once in neonatal mice (at P7; 10mg/kg). In turn, Δ9-THC or saline was administered sub-acutely later in life to cohorts of animals who had received either PCP or saline (P55-80, 5mg/kg). Mice who were administered PCP alone displayed behavioral changes in the Morris water waze (MWM) and pre-pulse inhibition (PPI) task paradigm that were consistent with schizophrenia-related phenotypes, but not in the locomotor activity or novel object recognition (NOR) task paradigms. Mice who were administered PCP and then received Δ9-THC later in life displayed behavioral changes in the locomotor activity paradigm (p<0.001) that was consistent with a schizophrenia-related phenotype, as well as potentiated changes in the NOR (p<0.01) and MWM (p<0.05) paradigms as compared to mice that received PCP alone. Decreased cortical receptor expression of NMDA receptor 1 subunit (NR1) was observed in mice that received PCP and PCP+Δ9-THC, while mice that received Δ9-THC and PCP+Δ9-THC displayed decreases in CB1 receptor expression. These findings suggest that administration of Δ9-THC during the early adulthood can potentiate the development of schizophrenia-related behavioral phenotypes induced by neonatal exposure to PCP in mice.