Neurochemical regulation of auditory information processing studied with EEG/MEG: application to schizophrenia

Cognitive impairments of attention, memory and executive functions are a fundamental feature of the pathophysiology of schizophrenia. The neurophysiological and neurochemical changes in the auditory cortex are shown to underlie cognitive impairmentsin schizophrenia patients. Functional state of the neural substrate of auditory information processing could be objectively and non-invasively probed with auditory event-related potentials (ERPs) and event- related fields (ERFs). In the current work, we explored the neurochemical effect on the neural origins of auditory information processing in relation to schizophrenia. By means of ERPs/ERFs we aimed to determine how neural substrates of auditory information processing are modulated by antipsychotic medication in schizophrenia spectrum patients (Studies I, II) and by neuropharmacological challenges in healthy human subjects (Studies III, IV). First, with auditory ERPs we investigated the effects of olanzapine (Study I) and risperidone (Study II) in a group of patients with schizophrenia spectrum disorders. After 2 and 4 weeks of treatment, olanzapine has no significant effects on mismatch negativity(MMN) and P300, which, as it has been suggested, respectively reflect preattentive and attention-dependent information processing. After 2 weeks of treatment, risperidone has no significant effect on P300, however risperidone reduces P200 amplitude. This latter effect of risperidone on neural resources responsible for P200 generation could be partly explained through the action of dopamine. Subsequently, we used simultaneous EEG/MEG to investigate the effects of memantine (Study III) and methylphenidate (Study IV) in healthy subjects. We found that memantine modulates MMN response without changing other ERP components. This could be interpreted as being due to the possible influence of memantine through the NMDA receptors on auditory change- detection mechanism, with processing of auditory stimuli remaining otherwise unchanged. Further, we found that methylphenidate does not modulate the MMN response. This finding could indicate no association between catecholaminergic activities and electrophysiological measures of preattentive auditory discrimination processes reflected in the MMN. However, methylphenidate decreases the P200 amplitudes. This could be interpreted as a modulation of auditory information processing reflected in P200 by dopaminergic and noradrenergic systems. Taken together, our set of studies indicates a complex pattern of neurochemical influences produced by the antipsychotic drugs in the neural substrate of auditory information processing in patients with schizophrenia spectrum disorders and by the pharmacological challenges in healthy subjects studied with ERPs and ERFs.

Juvenile neuronal ceroid lipofuscinosis; psychiatric symptoms, GAD-autoantibodies, and response to medication

Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative diseases in childhood. Its clinical onset, with visual failure as the first sign, is between the ages of 4 to 8 years. During the disease progress, epilepsy, motor symptoms, cognitive decline, and psychiatric symptoms become apparent. It leads to premature death between ages 15 and 30. Treatment consists of symptomatic drug administration and various forms of rehabilitation, but to date, no curative treatment exists. To gain a more comprehensive picture of psychiatric problems, symptoms were evaluated by the Child Behavior Checklist, the Teacher Report Form, and the Children s Depression Inventory. The JNCL patients had a great number of severe psychiatric symptoms, with wide inter-individual variability. The most common symptoms were social, thought, attention, and sleep problems, somatic complaints, and aggressive behaviour. Patients with psychotropic treatment had more problems than did those without psychotropic treatment, and female patients had more problems than did males. Between 10 and 20% of the patients reported depressive symptoms. In a 5-year follow-up, [123I]β-CIT SPECT and MRI revealed a tendency of decreasing serotonin transporter (SERT) availability and progressive brain atrophy. The correlation between changes in midbrain SERT and total brain volume was positive; no correlation appeared between SERT or brain atrophy and depressive symptoms. Thus, it seems likely that the low SERT availability is associated with progressive brain atrophy; it may also predispose towards depression, however. An open survey of psychotropic drugs and their efficacy was performed on JNCL patients in Finland. The most commonly used psychotropic drugs were the antidepressant citalopram and the antipsychotic risperidone. Their efficacy was good or satisfactory in the majority of cases and they seemed well tolerated. Quetiapine had a marked effect on one patient with a history of severe psychotic symptoms. Glutamate decarboxylase 65 autoantibodies (GAD65ab), found in JNCL patients, indicate that an immunomediated reaction against GAD or GABAergic neurons may play a part in the underlying pathogenetic mechanism. GAD65ab s also appeared in the serum of all eight JNCL patients included and intermittent corticosteroid therapy was initiated in all cases. After one year, the GAD65ab s had disappeared in the two oldest patients, who experienced an improvement in motor symptoms and alertness associated with their prednisolone therapy. Two younger patients experienced a significant IQ increase, but no change in GADab s. A randomized study with longer follow-up time is needed, however, to clarify the effect of prednisolone on disease progression.

Biological mechanisms behind clozapine-induced agranulocytosis

Clozapine is the most effective drug in treating therapy-resistant schizophrenia and may even be superior to all other antipsychotics. However, its use is limited by a high incidence (approximately 0.8%) of a severe hematological side effect, agranulocytosis. The exact molecular mechanism(s) of clozapine-induced agranulocytosis is still unknown. We investigated the mechanisms behind responsiveness to clozapine therapy and the risk of developing agranulocytosis by performing an HLA (human leukocyte antigens) association study in patients with schizophrenia. The first group comprised patients defined by responsiveness to first-generation antipsychotics (FGAs) (n= 19). The second group was defined by a lack of response to FGAs but responsiveness to clozapine (n=19). The third group of patients had a history of clozapine-induced granulocytopenia or agranulocytosis (n=26). Finnish healthy blood donors served as controls (n= 120). We found a significantly increased frequency of HLA-A1 among patients who were refractory to FGAs but responsive to clozapine. We also found that the frequency of HLA-A1 was low in patients with clozapine-induced neutropenia or agranulocytosis. These results suggest that HLA-A1 may predict a good therapeutic outcome and a low risk of agranulocytosis and therefore HLA typing may aid in the selection of patients for clozapine therapy. Furthermore, in a subgroup of schizophrenia, HLA-A1 may be in linkage disequilibrium with some vulnerability genes in the MHC (major histocompatibility complex) region on chromosome 6. These genes could be involved in antipsychotic drug response and clozapine-induced agranulocytosis. In addition, we investigated the effect of clozapine on gene expression in granulocytes by performing a microarray analysis on blood leukocytes of 8 schizophrenic patients who had started clozapine therapy for the first time. We identified an altered expression in 4 genes implicated in the maturation or apoptosis of granulocytes: MPO (myeloperoxidase precursor), MNDA (myeloid cell nuclear differentiation antigen), FLT3LG (Fms-related tyrosine kinase 3 ligand) and ITGAL (antigen CD11A, lymphocyte function-associated antigen 1). The altered expression of these genes following clozapine administration may suggest their involvement in clozapine-induced agranulocytosis. Finally, we investigated whether or not normal human bone marrow mesenchymal stromal cells (MSC) are sensitive to clozapine. We treated cultures of human MSCs and human skin fibroblasts with 10 µM of unmodified clozapine and with clozapine bioactivated by oxidation. We found that, independent of bioactivation, clozapine was cytotoxic to MSCs in primary culture, whereas clozapine at the same concentration stimulated the growth of human fibroblasts. This suggests that direct cytotoxicity to MSCs is one possible mechanism by which clozapine induces agranulocytosis.

Pitfalls in the Treatment of Persons with Dementia

Pitfalls in the treatment of persons with dementia Persons with dementia require high-quality health care, rehabilitation and sufficient social services to support their autonomy and to postpone permanent institutionalization. This study sought to investigate possible pitfalls in the care of patients with dementia: hip fracture rehabilitation, use of inappropriate or antipsychotic medication, social and medicolegal services offered to dementia caregiving families. Three different Finnish samples were used from years 1999-2005, mean age 78 to 86 years. After hip fracture operation, the weight-bearing restriction especially in group of patients with dementia, was associated with a longer rehabilitation period (73.5 days vs. 45.5 days, p=0.03) and the inability to learn to walk after six weeks (p<0.001). Almost half (44%) of the pre-surgery home-dwellers with dementia in our sample required permanent hospitalization after hip fracture. Potentially inappropriate medication was used among 36.2% of nursing home and hospital patients. The most common PIDs in Finland were temazepam over 15 mg/day, oxybutynin, and dipyridamole. However, PID use failed to predict mortality or the use of health services. Nearly half (48.4%) of the nursing home and hospital patients with dementia used antipsychotic medication. The two-year mortality did not differ among the users of conventional or atypical antipsychotics or the non-users (45.3% vs.32.1% vs.49.6%, p=0.195). The mean number of hospital admissions was highest among non-users (p=0.029). A high number of medications (HR 1.12, p<0.001) and the use of physical restraints (HR 1.72, p=0.034) predicted higher mortality at two years, while the use of atypical antipsychotics (HR 0.49, p=0.047) showed a protective effect, if any. The services most often offered to caregiving families of persons with Alzheimer s disease (AD) included financial support from the community (36%), technical devices (33%), physiotherapy (32%), and respite care in nursing homes (31%). Those services most often needed included physiotherapy for the spouse with dementia (56%), financial support (50%), house cleaning (41%), and home respite (40%). Only a third of the caregivers were satisfied with these services, and 69% felt unable to influence the range of services offered. The use of legal guardians was quite rare (only 4.3%), while the use of financial powers of attorney was 37.8%. Almost half (47.9%) of the couples expressed an unmet need for discussion with their doctor about medico-legal issues, while only 9.9% stated that their doctor had informed them of such matters. Although we already have many practical methods to develop the medical and social care of persons with AD, these patients and their families require better planning and tailoring of such services. In this way, society could offer these elderly persons better quality of life while economizing on its financial resources. This study was supported by Social Insurance Institution of Finland and part of it made in cooperation with the The Central Union of the Welfare for the Aged, Finland.

The relationships between work stressors and organizational performance in long-term care for elderly residents

This study investigates the relationships between work stressors and organizational performance in terms of the quality of care provided by the long-term care facilities. Work stressors are first examined in relation to the unit's structural factors, resident characteristics, and to the unit specialization. The study is completed by an investigation into the associations of work stressors such as job demands or time pressure, role ambiguity, resident-related stress, and procedural injustice to organizational performance. Also the moderating effect of job control in the job demands organizational performance relationship is examined. The study was carried out in the National Research and Development Centre for Welfare and Health (STAKES). Survey data were drawn from 1194 nursing employees in 107 residential-home and health-center inpatient units in 1999 and from 977 employees in 91 units in 2002. Information on the unit resident characteristics and the quality of care was provided by the Resident Assessment Instrument (RAI). The results showed that large unit size or lower staffing levels were not consistently related to work stressors, whereas the impairments in residents' physical functioning in particular initiated stressful working conditions for employees. However, unit specialization into dementia and psychiatric residents was found to buffer the effects that the resident characteristics had on employee appraisals of work stressors, in that a high proportion of behavioral problems was related to less time pressure and role conflicts for employees in specialized units. Unit specialization was also related to improved team climates and the organizational commitment of employees. Work stressors associated with problems in care quality. Time pressure explained most of the differences between units in how the employees perceived the quality of physical and psychosocial care they provide for the residents. A high level of job demands in the unit was also found to be related to some increases in all clinical quality problems. High job control buffered the effects of job demands on the quality of care in terms of the use of restraints on elderly residents. Physical restraint and especially antipsychotic drug use were less prevalent in units that combined both high job demands and high control for employees. In contrast, in high strain units where heavy job demands coincided with a lack of control for employees, quality was poor in terms of the frequent use of physical restraints. In addition, procedural injustice was related to the frequent use of antianxiety of hypnotic drugs for elderly residents. The results suggest that both job control and procedural justice may have improved employees' abilities to cope when caring for the elderly residents, resulting in better organizational performance.