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Background Schizophrenia is a lifelong illness that requires long-term treatment and caregiving. Family psychoeducation (FP) has been shown to lessen caregiver burden, improve caregiver functioning, and improve outcomes in patients. However, the impact of FP delivered specifically to caregivers on patient outcomes has not been well explored, particularly for early schizophrenia. Furthermore, there is a lack of research examining the benefits of telehealth-based psychoeducation for caregivers on either patient or caregiver outcomes. Objective The Family Intervention in Recent-Onset Schizophrenia Treatment (FIRST) study is a randomized controlled trial of patients with schizophrenia spectrum disorders and their caregivers, which is designed to evaluate the effect of telehealth-based, caregiver-focused, study-provided psychoeducation versus usual care (UC) on patient treatment failure (TF). The impact of study-provided psychoeducation on caregiver burden is also investigated. Methods Eligible patients and their designated caregivers were randomly assigned to either the study-provided psychoeducation (≤16 sessions of telehealth-based psychoeducation over 6 months) or UC group, stratified by antipsychotic treatment (paliperidone palmitate or oral antipsychotic). The major TF events (ie, psychiatric hospitalization or intervention, arrest or incarceration, and suicide attempts) were assessed at 3, 6, and 12 months after baseline. A proportional means model using mean cumulative function was used to assess between-group differences in the mean cumulative number of TF events over 12 months. Caregiver burden was assessed using the Involvement Evaluation Questionnaire and 12-item Short Form Health Survey. Results A total of 148 pairs of participants were enrolled in the study, of whom 96 (64.9%) patients and 94 (63.5%) caregivers completed the 12-month follow-up. The mean number of sessions in the study-provided psychoeducation group was 7.7 (SD 5.9). No differences were observed between the study-provided psychoeducation and UC groups in patient outcomes (rates of TF: 70% vs 67%; P=.90) or measures of caregiver burden (assessment of caregiver distress and physical and mental health). However, post hoc analyses revealed lower relapse rates in patients who received paliperidone palmitate than in those who received oral antipsychotics at all time points. Although the FIRST study did not meet the primary end point, several key lessons were identified to inform future caregiver-focused, telehealth-based FP interventions. Lack of study-provided psychoeducation, focus on caregiver-only intervention, difficulties with enrollment, and caregiver–treatment team coordination may have affected the outcomes of the FIRST study. Conclusions Key insights from the FIRST study suggest the potential importance of supporting sufficient caregiver engagement; communication between clinicians, patients, and family members regarding treatment plans; and solidifying the relationship between clinicians providing psychoeducation to the caregiver and patient treatment team. Trial Registration ClinicalTrials.gov NCT02600741; http://clinicaltrials.gov/ct2/show/NCT02600741

Aim This exploratory post hoc analysis of a randomized, double‐blind (DB), multicentre, non‐inferiority study (NCT01515423) evaluated the effects of the long‐acting injectable antipsychotic therapies once‐monthly paliperidone palmitate (PP1M) and once‐every‐3‐months paliperidone palmitate (PP3M) on symptom severity and functional remission in patients with schizophrenia with differing durations of illness (≤5, 6‐10 and >10 years). Methods Endpoints included Personal and Social Performance (PSP) scale and Positive and Negative Syndrome Scale (PANSS) total scores during the DB phase (DB baseline and DB endpoint) and the proportion of patients meeting PSP or PANSS remission criteria at any time during the open‐label (OL) or DB phases that were maintained for ≥3, ≥6, ≥9 or ≥12 months. Results In both the OL and DB phases, significant improvements in PSP scale and PANSS scores were observed from baseline in all duration‐of‐illness groups, with significantly greater improvements observed in the ≤5‐year and 6‐10‐year groups compared with the >10‐year group. The proportion of patients who maintained PSP or PANSS remission criteria for ≥3, ≥6, ≥9 and ≥12 months was higher in the ≤5‐year and 6‐10‐year groups than in the >10‐year group. Safety profiles were similar across duration‐of‐illness groups in the DB phase. Conclusions Symptomatic and functional improvements were observed with PP1M/PP3M in patients with differing durations of schizophrenia, but the magnitude of the effects was greater in those with early illness vs chronic illness. These findings advocate implementation of PP1M and PP3M in all stages of schizophrenia, including early illness.

Schizophrenia is a chronic, serious mental illness (SMI) that affects approximately 1.1% of the population aged ≥18 years. There are approximately 8.4 million caregivers of US adults with SMI. Caregivers can provide vital support, but the burden and distress caused by recurrent SMI symptomatology are barriers to effective caregiving. The aim of this analysis is to describe the demographic and baseline characteristics of caregivers and patients with recent-onset schizophrenia, schizoaffective disorder, or schizophreniform disorders enrolled in the Family Intervention in Recent-Onset Schizophrenia Treatment (FIRST) study (NCT02600741) and evaluate the correlation between caregiver burden and severity of patient illness. FIRST is a 12-month, ongoing, prospective, randomized study to evaluate the effect of a caregiver-directed psychosocial intervention on outcomes in patients with recent-onset schizophrenia, schizoaffective disorder, or schizophreniform disorders receiving paliperidone palmitate (PP) or oral antipsychotic treatment (OAT). The caregivers were randomized into 2 study groups (usual caregiver support or study-provided caregiver-directed psychosocial intervention) within strata defined by the type of antipsychotic medication (PP or OAT) that patients were prescribed by their treating physicians. The patients were assessed for symptom severity (CGI-S) and illness management and recovery. The caregivers were assessed for caregiver burden (IEQ), general health (SF-12), and health-care resource utilization. The study is ongoing and the current analysis is based on interim data from 52 patient–caregiver pairs. Patients were predominantly male (84.6%), were white (57.6%), black (36.5%), and had a mean age of 25.3 years; 9.6% were Hispanic. Most (88.5%) patients lived at home with family or friends. The average CGI-S score for patients receiving PP was 4.94 and for patients receiving OAT was 3.89. Caregivers were predominantly female (76.9%), were mostly parents (86.5%), and had a mean age of 52.4 years. There was a moderate yet significant correlation between the IEQ total score and patients’ CGI-S score at baseline ( = .36, = .011). The correlation between the total IEQ score and the patient’s or caregiver’s age, gender, and race was not significant. The interim analysis of the baseline data showed that greater severity of patient illness is correlated with higher caregiver burden.Reference 1. National Alliance for Caregiving. www.caregiving.org. 2016. Accessed October 11, 2016.

Postmortem and in vivo studies of schizophrenia frequently reveal reduced cortical volume, but the underlying cellular abnormalities are incompletely defined. One influential hypothesis, especially investigated in Brodmann’s area 9 of prefrontal cortex, is that the number of neurons is normal, and the volume change is caused by reduction of the surrounding neuropil. However, studies have differed on whether the cortex has the increased neuron density that is predicted by this hypothesis. In a recent study of bilateral planum temporale (PT), we reported smaller volume and width of the outer cortex (layers I-III), especially in the left hemisphere, among subjects with schizophrenia. In the present study, we measured neuron density and size in the same PT samples, and also in prefrontal area 9 of the same brains. In the PT, separate stereological measurements were made in layers II, IIIc, and VI, whereas area 9 was sampled in layer IIIb-c. In both cortical regions, there was no significant effect of schizophrenia on neuronal density or size. There was, nevertheless, a trend-level right>left hemispheric asymmetry of neuron density in the PT, which may partially explain the previously reported left>right asymmetry of cortical width. In schizophrenia, our findings suggest that closer packing of neurons may not always explain reduced cortical volume, and subtly decreased neuron number may be a contributing factor.

The anterior limb of the internal capsule (ALIC) is the major white matter tract providing reciprocal connections between the frontal cortex, striatum and thalamus. Mounting evidence suggests that this tract may be affected in schizophrenia, with brain imaging studies reporting reductions in white matter volume and density, changes in fractional anisotropy and reduced asymmetry. However, the molecular correlates of these deficits are currently unknown. The aim of this study was to identify alterations in protein and metabolite levels in the ALIC in schizophrenia. Samples were obtained post-mortem from individuals with schizophrenia (n=15) and non-psychiatric controls (n=13). Immunoreactivity for the myelin-associated protein myelin basic protein (MBP), and the axonal-associated proteins phosphorylated neurofilament and SNAP-25 was measured by enzyme-linked immunoadsorbent assay (ELISA). Metabolite concentrations were quantified by proton nuclear magnetic resonance ((1)H NMR) spectroscopy. Levels of myelin- or axonal-associated proteins did not differ between groups. Overall differences in metabolite concentrations were observed between the two groups (MANOVA F=2.685, p=0.036), with post-hoc tests revealing lower lactate (19%) and alanine (24%) levels in the schizophrenia group relative to controls. Observed changes in lactate and alanine levels indicate metabolic abnormalities within the ALIC in schizophrenia.

The Scales of Cognitive Impairment Rated From Institutional Records (SCIRFIR), a battery based on commonly used dementia rating instruments, was tested on the records of 26 chronically institutionalized, elderly schizophrenia patients, for the purpose of retrospectively evaluating the long-term course of cognitive change in schizophrenia and relating it to available autopsy materials. The inter-rater reliability of the component scales was high (Intraclass Correlations=0.78–0.96), the final item scores were comparable to ratings on living subjects, and Alzheimer-type neuropathological changes were associated with a markedly deteriorating course. The substantial potential of this method is discussed.

In vivo structural MRI studies in schizophrenia auditory cerebral cortex have reported smaller volumes and, less consistently, have reported altered hemispheric asymmetry of volumes. We used autopsy brains from 19 schizophrenia and 18 nonpsychiatric male subjects to measure the volume asymmetry of the planum temporal (PT). We then used the most recently autopsied 11 schizophrenia and 10 nonpsychiatric brains to measure the widths and fractional volumes of the upper (I-III) and lower (IV-VI) layers. Measurements of whole PT gray matter volumes did not show significant changes in schizophrenia. Nevertheless, laminar volume measurements revealed that the upper layers of the PT comprise a smaller fraction of the total cortex in schizophrenia than in nonpsychiatric brains. Subdivision of the PT showed that this change was especially prominent caudally, beyond Heschl's gyrus, whereas similar but less pronounced changes were found in the rostral PT and Heschl's gyrus. Complementary measures of laminar widths showed that the altered fractional volume in the caudal left PT was due mainly to approximately 8% thinner upper layers. However, the caudal right PT had a different profile, with thicker lower layers and comparatively unchanged upper layers. Thus, in the present study, laminar measurements provided a more sensitive method for detecting changes than measurement of whole PT volumes. Besides findings in schizophrenia, our cortical width measurements revealed normal hemispheric asymmetries consistent with previous reports. In schizophrenia, the thinner upper layers of the caudal PT suggest disrupted corticocortical processing, possibly affecting the multisensory integration and phonetic processing of this region.

Abnormalities of cerebral white matter, oligodendrocytes, and myelin have been observed in schizophrenia with in-vivo imaging and post-mortem biochemistry. White-matter abnormalities are also frequently associated with cognitive impairment in both healthy and diseased individuals, and cognitive dysfunction is an important component of schizophrenia. While many studies have documented these associations, only a handful have examined the role of white matter in cognitive function in schizophrenia. In this paper, we explore what is known about white-matter deficits in relation to schizophrenia, cognitive deficits, or both together, in order to generate a theoretical model for the role that compromise of white matter might play in producing cognitive impairment in schizophrenia.