Feasibility study to evaluate capabilities for conducting psychiatric clinical research within the Rwandan mental healthcare system.

OBJECTIVE: To evaluate the feasibility of conducting a large clinical trial within the Rwandan mental healthcare system that would establish the safety, efficacy and benefit of paliperidone palmitate once-monthly (PP1M) and once-every-3-months (PP3M) long-acting injectable formulations in adults with schizophrenia. STUDY DESIGN: An open-label, prospective feasibility study. SETTING/PARTICIPANTS: 33 adult patients with schizophrenia were enrolled at 3 sites across Rwanda. INTERVENTIONS: The study design included 3 phases of treatment: an oral run-in to establish tolerability to risperidone (1 week), lead-in treatment with flexibly dosed PP1M to identify a stable dose (17 weeks) and maintenance treatment with PP3M (24 weeks). PRIMARY AND SECONDARY OUTCOME MEASURES: Feasibility endpoints included compliance with governmental and institutional requirements, acceptable supply chain delivery and proper onsite administration of risperidone/PP1M/PP3M, adequate site infrastructure, adequate training of clinical staff and successful completion of study procedures and scales. A variety of study scales were administered to assess outcomes relevant to patients, caregivers, clinicians and payers in Rwanda and other resource-limited settings. RESULTS: This study was terminated early by the sponsor because certain aspects of study conduct needed to be addressed to maintain Good Clinical Practice requirements and meet regulatory standards. Results identified areas for improvement in study execution, including study governance, site infrastructure, study preparation and conduct of procedures, study budget and study assessments. Despite the identification of areas in need of adjustment, none of these limitations were considered insurmountable. CONCLUSIONS: This work was designed to strengthen global research in schizophrenia by building the capacity of researchers to prepare and conduct pharmaceutical trials in resource-limited settings. Although the study was ended early, modifications motivated by the results will facilitate the successful design and completion of more comprehensive studies, including an ongoing, follow-up interventional trial of PP1M/PP3M in a larger population of patients in Rwanda. TRIAL REGISTRATION NUMBER: NCT03713658.

Telehealth-Based Psychoeducation for Caregivers: The Family Intervention in Recent-Onset Schizophrenia Treatment Study.

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.

Evaluation of paliperidone palmitate long-acting injectable antipsychotic therapy as an early treatment option in patients with schizophrenia.

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.

Hemispheric comparisons of neuron density in the planum temporale of schizophrenia and nonpsychiatric brains.

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.

A novel mechanism and treatment target for presynaptic abnormalities in specific striatal regions in schizophrenia.

Abnormalities of amount and function of presynaptic terminals may have an important role in the mechanism of illness in schizophrenia. The SNARE proteins (SNAP-25, syntaxin, and VAMP) are enriched in presynaptic terminals, where they interact to form a functional complex to facilitate vesicle fusion. SNARE protein amounts are altered in the cortical regions in schizophrenia, but studies of protein-protein interactions are limited. We extended these investigations to the striatal regions (such as the nucleus accumbens, ventromedial caudate (VMC), and dorsal caudate) relevant to disease symptoms. In addition to measuring SNARE protein levels, we studied SNARE protein-protein interactions using a novel ELISA method. The possible effect of antipsychotic treatment was investigated in parallel in the striatum of rodents that were administered haloperidol and clozapine. In schizophrenia samples, compared with controls, SNAP-25 was 32% lower (P=0.015) and syntaxin was 26% lower (P=0.006) in the VMC. In contrast, in the same region, SNARE protein-protein interactions were higher in schizophrenia (P=0.008). Confocal microscopy of schizophrenia and control VMC showed qualitatively similar SNARE protein immunostaining. Haloperidol treatment of rats increased levels of SNAP-25 (mean 24%, P=0.003), syntaxin (mean 18%, P=0.010), and VAMP (mean 16%, P=0.001), whereas clozapine increased only the VAMP level (mean 13%, P=0.004). Neither drug altered SNARE protein-protein interactions. These results indicate abnormalities of amount and interactions of proteins directly related to presynaptic function in the VMC in schizophrenia. SNARE proteins and their interactions may be a novel target for the development of therapeutics.

Altered volume and hemispheric asymmetry of the superficial cortical layers in the schizophrenia planum temporale.

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.

Metabolic abnormalities in fronto-striatal-thalamic white matter tracts in schizophrenia.

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.

White matter and cognitive function in schizophrenia.

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.

Lifelong course of positive and negative symptoms in chronically institutionalized patients with schizophrenia.

BACKGROUND: Despite widespread policies of deinstitutionalization, a substantial number of patients with schizophrenia require continuous custodial care. The hospital records of such patients provide contemporaneous documentation of symptoms throughout the illness, permitting a longitudinal study of the course of symptoms. We sought to describe this course, and to determine the influences of sex, age of onset, and treatment on its evolution. METHODS: Using the modified Diagnostic Evaluation After Death, we performed standardized chart reviews of 99 chronic inpatients who remained in state institutions through the 1960's and 1970's and subsequently died in those institutions. Data were available from the onset of illness until death. RESULTS: We found significant decreases in positive symptoms and increases in negative symptoms over the course of the illness. Symptom patterns were analyzed by repeated measures ANOVA. Onset before age 25 was associated with greater numbers of negative symptoms at a given age (p = 0.05). Female sex was associated with greater numbers of positive symptoms (p=0.04). The widespread introduction of neuroleptic drugs in the mid-1950's did not affect the trends in symptom patterns. CONCLUSIONS: The lifetime course of schizophrenia in chronically institutionalized individuals is characterized by a decrease in positive symptoms and an increase in negative symptoms. Schizophrenia with earlier onset is associated with greater numbers of negative symptoms throughout life. In this sample of patients, chronically hospitalized until death, neuroleptic drugs failed to effect a persistent decrease in positive symptoms.

Altered subicular MAP2 immunoreactivity in schizophrenia.

We wished to test independently a previously reported loss of subicular microtubule-associated protein 2 (MAP2) in the brains of deceased individuals who had suffered from schizophrenia, and to determine whether there were any clinical characteristics attached to such a loss. Immunohistochemistry for MAP2 was examined in the hippocampal region from 94 psychiatric patients: 64 with a primary diagnosis of schizophrenia or schizoaffective disorder, 12 with a primary diagnosis of major depressive or bipolar disorders, and 18 with a primary diagnosis of dementia; and from 17 individuals without psychiatric disease. Lifelong symptomatology was evaluated with the modified Diagnostic Evaluation After Death. Subicular MAP2 immunoreactivity was prominently depressed in 20% of schizophrenia cases, 8% of mood disorder cases, 22% of dementia cases, and in no nonpsychiatric cases. Among dementia cases, those with loss of subicular MAP2 immunoreactivity displayed more subicular gliosis, while among the schizophrenia cases, there was no such association. Among schizophrenia subjects, loss of subicular MAP2 immunoreactivity was associated with fewer positive and negative symptoms over the course of the illness. Subicular MAP2 immunoreactivity is markedly diminished in a significant proportion of individuals chronically institutionalized for schizophrenia, and this does not represent a generalized destruction of subicular neurons. In contrast, among individuals institutionalized for dementia, loss of subicular MAP2 immunoreactivity is accompanied by gliosis. The loss of MAP2 immunoreactivity is associated with fewer clinical symptoms, suggesting that it may represent an adaptive response to schizophrenia. The chemical or structural abnormalities underlying decreased MAP2 immunoreactivity in schizophrenia remain to be determined.

Optimization of Golgi methods for impregnation of brain tissue from humans and monkeys.

Golgi impregnation is unique in its ability to display the dendritic trees of large numbers of individual neurons. However, its reputation for inconsistency leaves many investigators reluctant to embrace this methodology, particularly for the study of formalin-fixed human brain tissue. After reviewing the literature, testing a variety of technical variations, and discussing the procedure with experienced practitioners, we have concluded that much of the unpredictability can be removed by matching the Golgi technique to the conditions that were used for fixation of the tissue. Briefly fixed tissues worked best with the rapid Golgi technique, which includes osmium during the initial chromation step, and with the Golgi-Cox method, which includes mercuric chloride during chromation. For tissues that have been fixed for several years or even for several decades, superior results are obtained with the Golgi-Kopsch technique, using multiple changes of a chromation solution that contains paraformaldehyde. In the Golgi-Kopsch technique, pH should be used to monitor the reduction of Cr6+ to Cr3+, which is a crucial determinant of successful chromation. With any Golgi technique, agitation throughout the impregnation helps to avoid precipitates and to improve the quality of impregnation. When the appropriate method is chosen, Golgi impregnation is a useful technique for the neuropathologist.