Lena Flyckt

Meta-analysis of cognitive performance in drug-naïve patients with schizophrenia

Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority of the clinical studies have been conducted in antipsychotic drug treated patients. Thus, it remains unclear if significant cognitive impairments exist in the absence of medication. This is the first meta-analysis of cognitive findings in drug-naïve patients with schizophrenia. Cognitive data from 23 studies encompassing 1106 patients and 1385 controls published from 1992 to 2013 were included. Tests were to a large extent ordered in cognitive domains according to the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery. Analysis was performed with STATA using the random-effects model and heterogeneity as well as Eggers publication bias was assessed. Overall the results show that patients performed worse than healthy controls in all cognitive domains with medium to large effect sizes. Verbal memory, speed of processing and working memory were three of the domains with the greatest impairments. The pattern of results is in line with previous meta-analytic findings in antipsychotic treated patients. The present meta-analysis confirms the existence of significant cognitive impairments at the early stage of the illness in the absence of antipsychotic medication.

Clinical and biochemical effects of citalopram, a selective 5-HT reuptake inhibitor — a dose-response study in depressed patients

Citalopram is a bicyclic phtalane derivative. In animal experiments, citalopram has been demonstrated to possess a potent and highly selective inhibitory effect on serotonin reuptake. Several studies in man have indicated that citalopram given in daily doses of 40–60 mg has antidepressant properties and few side effects. The present double-blind study investigated the effects of three doses of citalopram (5 mg, 25 mg, and 50 mg) on depressive symptoms and various biochemical variables in 26 depressive patients. A significant reduction of the clinical ratings of depressive symptoms occurred at all dose levels. In endogenously depressed patients, a dose of 25 or 50 mg daily seemed to have the most pronounced antidepressive effect. The side effects were few and not related to dose level. A highly significant decrease in 5-HIAA in the CSF was found. MOPEG in the CSF was also significantly decreased, while HVA in the CSF was increased. In addition, a significant decrease in the plasma concentrations of valine, leucine, tyrosine, and histidine was found. None of the biochemical effects was dose-dependent. The complex pattern of biochemical effects indicate that the amelioration of depressive symptoms might be related to effects of citalopram on central monoaminergic mechanisms and peripheral amino acid concentrations.

Burden of informal care giving to patients with psychoses: A descriptive and methodological study

Background: There is a lack of studies of the size of burden associated with informal care giving in psychosis. Aims: To evaluate the objective and subjective burden of informal care giving to patients with psychoses, and to compare a diary and recall method for assessments of objective burden. Method: Patients and their informal caregivers were recruited from nine Swedish psychiatric outpatient centres. Subjective burden was assessed at inclusion using the CarerQoL and COPE index scales. The objective burden (time and money spent) was assessed by the caregivers daily using diaries over four weeks and by recall at the end of weeks 1 and 2. Results: One-hundred and seven patients (53% females; mean age 43 ± 11) and 118 informal caregivers (67%; 58 ± 15 years) were recruited. Informal caregivers spent 22.5 hours/week and about 14% of their gross income on care-related activities. The time spent was underestimated by two to 20 hours when assessed by recall than by daily diary records. The most prominent aspects of the subjective burden were mental problems. Conclusion: Despite a substantial amount of time and money spent on care giving, the informal caregivers perceived the mental aspects of burden as the most troublesome. The informal caregiver burden is considerable and should be taken into account when evaluating effects of health care provided to patients with psychoses.

Lower levels of the glial cell marker TSPO in drug-naive first-episode psychosis patients as measured using PET and |[lsqb]|11C|[rsqb]|PBR28

Several lines of evidence are indicative of a role for immune activation in the pathophysiology of schizophrenia. Nevertheless, studies using positron emission tomography (PET) and radioligands for the translocator protein (TSPO), a marker for glial activation, have yielded inconsistent results. Whereas early studies using a radioligand with low signal-to-noise in small samples showed increases in patients, more recent studies with improved methodology have shown no differences or trend-level decreases. Importantly, all patients investigated thus far have been on antipsychotic medication, and as these compounds may dampen immune cell activity, this factor limits the conclusions that can be drawn. Here, we examined 16 drug-naive, first-episode psychosis patients and 16 healthy controls using PET and the TSPO radioligand [11C]PBR28. Gray matter (GM) volume of distribution (VT) derived from a two-tissue compartmental analysis with arterial input function was the main outcome measure. Statistical analyses were performed controlling for both TSPO genotype, which is known to affect [11C]PBR28 binding, and gender. There was a significant reduction of [11C]PBR28 VT in patients compared with healthy controls in GM as well as in secondary regions of interest. No correlation was observed between GM VT and clinical or cognitive measures after correction for multiple comparisons. The observed decrease in TSPO binding suggests reduced numbers or altered function of immune cells in brain in early-stage schizophrenia.

Muscle biopsy, macro EMG, and clinical characteristics in patients with schizophrenia

Abstract Background: In a previous study of motor unit properties in patients with schizophrenia, muscle fiber histologic and electrophysiologic abnormalities were observed. The present study was designed to compare patients with schizophrenia with healthy control subjects with regard to muscle fiber histology and motor unit function. A second objective was to relate these variables to clinical characteristics. Methods: Twelve patients with first-episode schizophrenia and fifteen patients with chronic schizophrenia (DSM-III-R) and 27 matched control subjects were included in the study. Muscle biopsies were performed either in m. tibialis anterior or m. vastus lateralis. Electromyographic recordings (macro EMG) were made from the m. tibialis anterior motor units. Psychiatric ratings included the PANSS and extrapyramidal side effects. Results: Seven of the muscle biopsy specimens from the patients and one from the control subjects were classified as abnormal ( p = .049). The most frequent abnormality was atrophic muscle fibers. Eight patients and no control subjects exhibited pathological macro EMG ( p = .032). The findings were present in chronic as well as in first-episode patients with schizophrenia. Conclusions: In approximately 50% of the patients, neuromuscular abnormalities were found either in the muscle biopsy or the macro EMG investigations.The results indicate that either a common pathologic process or different pathological processes are at hand in the neuromuscular system in patients with schizophrenia. The findings are compatible with a disturbed cell membrane function.

Kinetics of tyrosine transport and cognitive functioning in schizophrenia

BACKGROUND Tyrosine supplementation in humans has been shown to improve cognitive functioning. Several studies have demonstrated a decreased maximal transport capacity of tyrosine (Vmax) across the cell membrane and an increased affinity (Km) of tyrosine to membrane binding sites in schizophrenic patients. A lack of tyrosine for dopamine synthesis with impairment of dopaminergic transmission could impair cognitive functioning. Aberrant tyrosine kinetics in patients with schizophrenia might therefore be associated with cognitive dysfunction--a core feature of schizophrenia. METHODS Tyrosine kinetics was determined in cultured fibroblasts from 36 schizophrenic patients. The kinetic parameters Vmax and Km were calculated and then the patients were divided into two groups according to the median of the kinetic parameters. A comprehensive neuropsychological test battery was used to evaluate cognitive functioning. RESULTS Patients with low Km (below the median) had poorer cognitive performance than patients with high Km (above the median). Vmax did not discriminate schizophrenic patients with cognitive dysfunction to the same extent. CONCLUSIONS Changes in tyrosine transport probably influence cognitive functioning via the dopamine system. However, our findings of a relation between low Km and cognitive dysfunction may have a more complex background. It is suggested that the connection is related to genetically determined membrane factors that disturb communication/transmission among neurons.

Association study between dopamine D3 receptor gene variant and personality traits

Dopamine receptor gene variation has been hypothesized to influence personality traits characterized by novelty seeking and related traits. We analyzed a dopamine D3 receptor gene (DRD3) variant in a Swedish population (n = 373) investigated with one or more of several personality questionnaires. No significant relationships were found between DRD3 genotypes and any of the 15 Karolinska Scales of Personality (KSP) and five Health‐relevant Personality 5 factor inventory (HP5i) scales. The DRD3 variant was associated with some scales related to novelty seeking: the Swedish universities Scales of Personality (SSP) Adventure Seeking and the revised NEO personality inventory (NEO‐PI‐R) Fantasy (O1) and Order (C2) scales. There were also associations with the Temperament and Character Inventory (TCI) Cooperativeness and Compassion (C4) scales. After correction for multiple testing, however, no significant difference remained. We conclude that the investigated DRD3 polymorphism does not have a major impact on personality in the investigated population.

Functional characterization of tyrosine transport in fibroblast cells from healthy controls

Human fibroblast cells are an advantageous model to study the transport of amino acids across cell membranes, since one can control the environmental factors. A major problem in all earlier studies is the lack of precise and detailed knowledge regarding the expression and functionality of tyrosine transporters in human fibroblasts. This motivated us to perform a systematic functional characterization of the tyrosine transport in fibroblast cells with respect to the isoforms of system-L (LAT1, LAT2, LAT3, LAT4), which is the major transporter of tyrosine. Ten (n=10) fibroblast cell lines from healthy volunteers were included in the study. Uptake of L-[U-14C] tyrosine in fibroblasts was measured using the cluster tray method in the presence and absence of excess concentrations of various combinations of inhibitors. This study demonstrated that LAT1 is involved in 90% of total uptake of tyrosine and also around 51% of alanine. Not more than 10% can be accounted for by LAT2, LAT3 and LAT4 isoforms. LAT2 seems to be functionally weak in uptake of tyrosine while LAT3 and LAT4 contributed around 7%. 10% could be contributed by system-A (ATA2 isoform). Alanine consequently inhibited the tyrosine transport by up to 60%. Tyrosine transport through the LAT1 isoform has a higher affinity compared to system-L. In conclusion, the LAT1 isoform is the major transporter of tyrosine in human fibroblast cells. Competition between tyrosine and alanine for transport is shown to exist, probably between LAT1 and LAT2 isoforms. This study established fibroblast cells as a suitable experimental model for studying amino acid transport defects in humans.

Consistent Functional Connectivity Alterations in Schizophrenia Spectrum Disorder: A Multisite Study

Schizophrenia (SZ) is a severe mental illness with high heritability and complex etiology. Mounting evidence from neuroimaging has implicated disrupted brain network connectivity in the pathophysiology. However, previous findings are inconsistent, likely due to a combination of methodological and clinical variability and relatively small sample sizes. Few studies have used a data-driven approach for characterizing pathological interactions between regions in the whole brain and evaluated the generalizability across independent samples. To overcome this issue, we collected resting-state functional magnetic resonance imaging data from 3 independent samples (1 from Norway and 2 from Sweden) consisting of 182 persons with a SZ spectrum diagnosis and 348 healthy controls. We used a whole-brain data-driven definition of network nodes and regularized partial correlations to evaluate and compare putatively direct brain network node interactions between groups. The clinical utility of the functional connectivity features and the generalizability of effects across samples were evaluated by training and testing multivariate classifiers in the independent samples using machine learning. Univariate analyses revealed 14 network edges with consistent reductions in functional connectivity encompassing frontal, somatomotor, visual, auditory, and subcortical brain nodes in patients with SZ. We found a high overall accuracy in classifying patients and controls (up to 80%) using independent training and test samples, strongly supporting the generalizability of connectivity alterations across different scanners and heterogeneous samples. Overall, our findings demonstrate robust reductions in functional connectivity in SZ spectrum disorders, indicating disrupted information flow in sensory, subcortical, and frontal brain regions.

Determinants of subjective and objective burden of informal caregiving of patients with psychotic disorders

Background: In a previous study, the objective burden of informal caregiving to patients with psychotic disorders amounted to 22 hours/week, and the subjective burden was huge with predominately anxiety and depression as main symptoms. In this study, determinants of the informal caregiving burden are analyzed to find foci for interventions to ease the size of burden. Methods: Patients with psychotic disorders (n = 107) and their informal caregivers (n = 118) were included. They were assessed with a comprehensive battery of rating scales including patient and caregiver characteristics as well as the amount and quality of health-care provision. Results: A multiple linear regression analysis showed that the subjective burden was significantly lower when patients had higher levels of functioning and when the health status of the informal caregivers was good. No significant determinants were found for the objective burden, but an association was found between a higher socioeconomic status of the caregivers and the amount of money provided for the patient. An association was also found between a positive perception of caregiving and more hours spent on caregiving. Conclusion: The functioning level of the patients was the main determinant of the subjective burden of informal care. For the objective burden, no main determinant was found.