Patients' perspectives on three-monthly administration of antipsychotic treatment with paliperidone palmitate - a qualitative interview study.

INTRODUCTION: Three-monthly dosage of paliperidone palmitate entails longer time to relapse after discontinuation, is similarly tolerable and safe compared to monthly injections of paliperidone palmitate and is beneficial for the caregivers. However, few studies have so far explored in depth the patients' experiences with paliperidone palmitate medication every three months, or with switching from monthly to three-monthly injections of paliperidone palmitate. MATERIAL AND METHODS: A qualitative study based on individual interviews with persons with schizophrenia who receive three-monthly paliperidone palmitate in Norway, Sweden and Denmark. Data was analysed according to qualitative content analysis. RESULTS: Twenty-four patients, 16 men and 8 women, took part in individual interviews. The patients' mental health care professionals mainly recommended the switch to three-monthly paliperidone palmitate, and few or no disadvantages were described. According to the patients, three-monthly paliperidone palmitate had several advantages, such as less frequent injections, less administration and planning and less focus on the illness. In addition, the participants described feeling more stability, being more physically and socially active, and that improvement processes were supported. For some, the use involved practical and economic challenges, and some worried whether the medicine 'wore off' before the next injection. According to the patients, switching to three-monthly paliperidone palmitate did not influence the frequency or content of patients' interaction with health care professionals. CONCLUSION: Switching from monthly to three-monthly injections with paliperidone palmitate seems to be experienced as advantageous for patients with schizophrenia.

Aberrant Wnt signaling pathway in medial temporal lobe structures of Alzheimer's disease.

Cognitive decline is a cardinal feature of Alzheimer's disease (AD) predominantly linked to synaptic failure, disrupted network connectivity and neurodegeneration. A large body of evidence associates the Wnt pathway with synaptic modulation and cognitive processes, suggesting a potential role for aberrant Wnt signaling in cognitive impairment. In fact, altered expression of key Wnt pathway components has been found in brains of AD patients as well as AD animal models supporting a deregulated pathway in AD. The evidence for deregulated Wnt signaling in AD, however, remains sparse and focused on isolated Wnt pathway components. Here, we provide the first comprehensive pathway-focused evaluation of the Wnt pathway in the entorhinal cortex and hippocampus of AD brains. Our data demonstrate altered Wnt pathway gene expression at all levels of the pathway in both medial temporal lobe regions with the hippocampus exhibiting most pronounced changes. Furthermore, the Wnt pathway constituents Wnt7b and Tcf7l1/Tcf3 showed overlapping gene expression alterations across both medial temporal lobe structures, while ß-catenin was inversely expressed between brain regions. We also identified total protein alterations of the intracellular Wnt pathway signaling components ß-catenin, Gsk3ß and Tcf7l1/Tcf3 and the phosphorylation state of ß-catenin and Gsk3ß in the hippocampus suggestive of a link between AD and aberrant canonical activity. Alterations in Gsk3ß co-appeared with hippocampal kinase-targeted hyperphosphorylation at specific tau epitope in soluble pretangles and prominent tau aggregation exclusively in insoluble neurofibrillary tangles of AD subjects. The Wnt pathway-focused approach confirms altered Wnt signaling in the neurodegenerative AD brain and highlights the potential role of the pathway as a therapeutic target for the treatment of patients.

Differential expression of parvalbumin in neonatal phencyclidine-treated rats and socially isolated rats.

Decreased parvalbumin expression is a hallmark of the pathophysiology of schizophrenia and has been associated with abnormal cognitive processing and decreased network specificity. It is not known whether this decrease is due to reduced expression of the parvalbumin protein or degeneration of parvalbumin-positive interneurons (PV(+) interneurons). In this study, we examined PV(+) expression in two rat models of cognitive dysfunction in schizophrenia: the environmental social isolation (SI) and pharmacological neonatal phencyclidine (neoPCP) models. Using a stereological method, the optical fractionator, we counted neurons, PV(+) interneurons, and glial cells in the medial prefrontal cortex (mPFC) and hippocampus (HPC). In addition, we quantified the mRNA level of parvalbumin in the mPFC. There was a statistically significant reduction in the number of PV(+) interneurons (p = 0.021) and glial cells (p = 0.024) in the mPFC of neonatal phencyclidine rats, but not in SI rats. We observed no alterations in the total number of neurons, hippocampal PV(+) interneurons, parvalbumin mRNA expression or volume of the mPFC or HPC in the two models. Thus, as the total number of neurons remains unchanged following phencyclidine (PCP) treatment, we suggest that the decreased number of counted PV(+) interneurons represents a reduced parvalbumin protein expression below immunohistochemical detection limit rather than a true cell loss. Furthermore, these results indicate that the effect of neonatal PCP treatment is not limited to neuronal populations.

Healthcare resource utilization prior to suicide death or suicide attempt in patients with major depressive disorder-A Danish registry-based cohort study.

INTRODUCTION: Major depressive disorder (MDD) is associated with suicide events and with increased healthcare resource utilization (HRU). The aim was to analyze the pattern of HRU prior to death by suicide or suicide attempt in patients with MDD using national registries. METHODS: Danish adults with MDD, who died by suicide or had a first-time suicide attempt, were matched with MDD controls on age, sex, and MDD severity and analyzed for psychiatric and non-psychiatric hospital and private practitioner contacts, and prescriptions 1 year prior to the event. For individuals having a second suicide attempt, HRU prior to first and second suicide attempt was analyzed. RESULTS: Among 1061 individuals dying by suicide and 3759 individuals with suicide attempt, compared with their controls, the proportion with psychiatric hospitalization was more than 50% increased, mainly accounted for by acute contacts. The difference to the matched controls decreased with increasing MDD severity. Non-psychiatric HRU was increased as well. The proportion with psychiatric hospitalizations or ED visits was reduced prior to the second attempt compared with first attempt. CONCLUSION: Among individuals with MDD, psychiatric and non-psychiatric HRU was increased 1 year prior to suicide event. The proportion of individuals who had psychiatric HRU decreased from first to second suicide attempt.

Healthcare resource utilization in patients with treatment-resistant depression-A Danish national registry study.

OBJECTIVES: To investigate healthcare resource utilization (HRU) and associated costs by depression severity and year of diagnosis among patients with treatment-resistant depression (TRD) in Denmark. METHODS: Including all adult patients with a first-time hospital contact for major depressive disorder (MDD) in 1996-2015, TRD patients were defined at the second shift in depression treatment (antidepressant medicine or electroconvulsive therapy) and matched 1:2 with non-TRD patients. The risk of utilization and amount of HRU and associated costs including medicine expenses 12 months after the TRD-defining date were reported, comparing TRD patients with non-TRD MDD patients. RESULTS: Identifying 25,321 TRD-patients matched with 50,638 non-TRD patients, the risk of psychiatric hospitalization following TRD diagnosis was 138.4% (95%-confidence interval: 128.3-149.0) higher for TRD patients than for non-TRD MDD patients. The number of hospital bed days and emergency department (ED) visits were also higher among TRD patients, with no significant difference for somatic HRU. Among patients who incurred healthcare costs, the associated HRU costs for TRD patients were 101.9% (97.5-106.4) higher overall, and 55.2% (50.9-59.6) higher for psychiatric services than those of non-TRD patients. The relative differences in costs for TRD-patients vs non-TRD patients were greater for patients with mild depression and tended to increase over the study period (1996-2015), particularly for acute hospitalizations and ED visits. LIMITATIONS: TRD was defined by prescription patterns besides ECT treatments. CONCLUSION: TRD was associated with increased psychiatric-related HRU. Particularly the difference in acute hospitalizations and ED visits between TRD and non-TRD patients increased over the study period.

Stereological estimation of the total number of myelinated callosal fibers in human subjects.

Using the fractionator principle, the total number, density and diameter size of myelinated callosal fibers were estimated in the corpus callosum (CC) of 10 Danish males between 39 and 60years of age. All sampled brains had been used in previous quantitative studies, for example, studies of neocortical neuron number, and were selected to determine whether the variability in the neocortical neuron number correlated with the total number of myelinated callosal fibers. Middle-aged males had an average of 138×10(6) (coefficient of variance; CV=0.19) myelinated fibers, but did not show any correlation with the neocortical neuron number (r=0.25; P=0.49). The mean area of the CC was estimated to be 7.2cm(2) (CV=0.17), and showed a significant correlation with the number of callosal fibers (r=0.69, P=0.041). Additionally, an overall density decline from the anterior to the posterior region of the CC was observed, with an inverse relationship between the distribution of large and small fibers along the callosal axis. This study suggests that many mechanisms are involved in the development and determination of axonal projections across the CC that cannot simply be explained by the neocortical neuron number. Further, a positive correlation between callosal fibers and the CC area verifies that callosal fibers are the factor responsible for CC size. Finally, the number of callosal fibers and their diameters are distributed along the CC in a specific pattern that reflects interactions with different brain regions.

Treatment patterns in patients with treatment-resistant depression in Danish patients with major depressive disorder.

OBJECTIVE: To describe treatment patterns in patients with treatment-resistant depression (TRD) and major depressive disorder (MDD) stratified by depression severity and year of diagnosis. Patterns of treatment were also compared to country-specific guidelines. METHODS: All adults registered first time with a hospital contact due to MDD from 1996 through 2015 were identified and followed for all dispensed prescriptions of antidepressants, antipsychotics, lithium, initiation of electroconvulsive therapy (ECT), and psychotherapy in Danish registers 12 months before and after their hospital MDD diagnosis. TRD was characterized by two shifts in treatment. RESULTS: We identified 197,615 patients of whom 15% developed TRD. In total, 88% of patients started treatment with antidepressants or ECT. Selective serotonin reuptake inhibitors (SSRIs) were the most frequently used treatment during the study period and more than half (50.7%) of patients changed treatment at least once. Among patients with TRD, serotonin and noradrenaline reuptake inhibitors (SNRIs) were the most frequently used treatment (55.9%), and 37.0% initiated a new treatment the following year. SSRIs and SNRIs were part of most combinations of treatment, regardless of depression severity, year of diagnosis, or presence of TRD. CONCLUSION: 15% of patients met the criteria for TRD. Irrespective of patient characteristics and year of diagnosis, SSRIs and SNRIs are the most used treatments for depression, even after patients met the criteria for TRD. We confirm that guidelines for first treatment were followed for most patients diagnosed with MDD in Denmark, but for patients with TRD, choice of treatment was arbitrary.

"I live, I don't work, but I live a very normal life"-A qualitative interview study of Scandinavian user experiences of schizophrenia, antipsychotic medication, and personal recovery processes.

PURPOSE: To illuminate user experiences of schizophrenia, reasons for receiving antipsychotic medication, and encounters with mental health services. DESIGN AND METHODS: 24 semistructured qualitative research interviews with schizophrenia patients treated with 3-monthly paliperidone palmitate across Scandinavia were synthesized in qualitative content analysis. FINDINGS: Participants describe considerable challenges in everyday functioning. Simultaneously, they rate their current mental and physical well-being high and seem satisfied with their lives. These pathways indicate personal recovery. PRACTICE IMPLICATIONS: The participants emphasize the importance of trustful relations with healthcare professionals, therapeutic conversations, antipsychotic medication in a 3-monthly formulation, and support from relatives.

Application of immunohistochemistry in stereology for quantitative assessment of neural cell populations illustrated in the Göttingen minipig.

BACKGROUND: Stereology is the study of estimating geometric quantities. When successfully applied, the combination of immunohistochemistry (IHC) and stereology eliminates intra- and interobserver variability for cell type identification. METHODOLOGY/PRINCIPAL FINDINGS: We propose a method to validate existing antibody based cell type markers for stereological application. Comparison was made on the 100-days-old Göttingen minipig (G-mini) neocortex between estimates of total neuron number derived from Giemsa staining using morphological criteria and immunohistochemistry-based cell counting with NeuN. The mean total neuron numbers estimated by the two staining methods were not significantly different. Estimated quantities, including glial cell number, neocortical volume, cell densities and glial-to-neuron ratio were also presented. Additionally, we assessed other commonly used glial markers and discussed how to evaluate the advantages and disadvantages of these markers for stereological estimation of cell number. CONCLUSION/SIGNIFICANCE: The concordance in quantitative estimates of total neuron number derived from NeuN- and Giemsa-stained sections provides evidence for the sensitivity and specificity of NeuN as a neuronal marker in the G-mini. Although time-consuming, quantitative validation of IHC should always be considered in stereological studies if there is doubt of the sensitivity, specificity, or reproducibility of cell type markers. Inaccurate staining may cause both over- and underestimation of the total cell number and inflict considerable limitation when analyzing the results.