Citalopram is a bicyclic phtalane derivative. In animal experiments, citalopram has been demonstr... more 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. MO-PEG 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.
Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority o... more 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 Egger's 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.
Tyrosine supplementation in humans has been shown to improve cognitive functioning. Several studi... more 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. 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. 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. 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.
The aim of the present study was to investigate socioeconomic and demographic determinants of dir... more The aim of the present study was to investigate socioeconomic and demographic determinants of direct costs for psychiatric disorders in Sweden. The cost categories were inpatient and outpatient costs, and costs for psychopharmacological drugs. Two consecutive years, 2001 and 2002, were chosen as the study period. The study included all costs for admissions, visits and prescribed drugs for adults aged > or = 18 years in 2001 and 2002 in Sweden. These costs were aggregated and analysed at the county level. A multiple linear regression analysis was fitted to the data, and independent variables (i.e. predictors) were chosen on the basis of previous studies. All cost types (e.g. total, inpatient, outpatient and drug costs) were analysed separately in different models. Large variations in total direct psychiatric costs were found between county councils (for example, the total costs varied between euro112 and euro195 per capita in 2001). The results indicate that psychiatric outpatient care is less utilized in rural than in urban areas, and drugs are more often prescribed in rural areas than in urban areas. Areas with a high proportion of women and people aged 65 years and over are strong predictors of mental healthcare costs, i.e. variables showing that the higher the proportion, the lower the direct costs. Factors such as urbanization, gender, age and number of immigrants are reasons for differences in psychiatric direct costs. On the basis of these findings, it seems plausible to conclude that women, older patients and immigrants may benefit from specialized psychiatry, but that such healthcare does not seem to be provided in all regions.
To further evaluate the controversial putative association between a Ser9Gly variant in the first... more To further evaluate the controversial putative association between a Ser9Gly variant in the first exon of the dopamine D3 receptor gene (DRD3) and schizophrenia. Swedish patients with schizophrenia ( n=156) and control subjects ( n=463) were assessed for the DRD3 Ser9Gly variant. Meta-analyses including previous and the present Swedish case-control results were performed. No significant difference between the Swedish patients and controls were found, but there was an association between DRD3 Ser9Gly Ser/Ser and homozygous genotypes and response to anti-psychotic drugs. This finding was supported by an incomplete meta-analysis. In a meta-analysis of all case-control studies comprising 8761 subjects the association between DRD3 Ser9Gly homozygosity and schizophrenia ( =4.96, degree of freedom=1, p <0.05, odds ratio=1.10, 95% confidence interval=1.01-1.20) persisted. However, the previously proposed association between the Ser/Ser genotype and schizophrenia was not significant (chi2 =2.71, degree of freedom=1, p>0.05, odds ratio=1.08, 95% confidence interval=0.99-1.17). Whereas the present Swedish case-control analysis did not yield any evidence for association with the diagnosis, the present meta-analysis suggests that the DRD3 gene confer susceptibility to schizophrenia. Reasons for the discrepancies between prior studies are discussed.
Disturbances in catecholamine transmission have been implicated in schizophrenia. Dopamine beta-h... more Disturbances in catecholamine transmission have been implicated in schizophrenia. Dopamine beta-hydroxylase catalyses the conversion of dopamine to norepinephrine in noradrenergic cells. We attempted to investigate a putative functional promoter polymorphism in the dopamine beta-hydroxylase gene (DBH) for association with schizophrenia. Unrelated schizophrenic patients (n=155) and control subjects (n=436) were analysed with regard to the DBH -1021 C/T variant. No significant allele or genotype differences were found. The present results do not support a major involvement of the DBH gene in schizophrenia in the Swedish population investigated.
To identify clinical cues indicative of depression in medical records of cases in primary care wi... more To identify clinical cues indicative of depression in medical records of cases in primary care with undetected depression. Depressive disorders are common; the lifetime risk for men and women is 27% and 45%, respectively. Despite effective treatment methods such as antidepressants and cognitive behavioural therapy, depression often remains undiscovered in primary care, with great implications both on the individual and societal level. Clinical cues indicating depression were sought in medical records the year before an opportunistic screening for depression in primary care. In a previous study of 221 patients in the waiting room of a primary care centre during 10 randomly selected days, 45 (20%) showed signs of depression (MADRS-S ⩾ 12) and 60% of these were verified as having depressive disorders (Prime-MD). These 45 patients constitute the cases in the present study. Age- and gender-matched controls were selected among those who scored below the chosen cut-off level. Seventeen (38%) of the 45 cases compared with eight (18%) of the 45 controls had one or more cues [odds ratio (OR) 2.81; 95% confidence interval (CI): 1.06-7.43]. Sleep disturbance showed the greatest difference between cases and controls (OR 4.53; 95% CI: 1.17-17.55). A significant relationship was found between severity of depression, frequency of cues and lower functional level. Cues were twice as common in patients with undetected depression and their functional level was lower. A two-stage procedure, screening and a structured diagnostic interview, is recommended when sleep disturbances and lowered function are present.
Human fibroblast cells are an advantageous model to study the transport of amino acids across cel... more 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.
Radiological assessments of patients with symptoms of impaired cerebrospinal fluid (CSF) circulat... more Radiological assessments of patients with symptoms of impaired cerebrospinal fluid (CSF) circulation are usually based on observations of anatomical and functional alterations using computed tomography (CT) and radionuclide cisternography (RC). In order to define criteria of normality for these two techniques, 30 healthy volunteers have been studied. In the studies of CSF flow the radiopharmaceutical 99mTc-DTPA was used and single photon emission computed tomography (SPECT) was performed as a complement to planar scintigraphy. In 16 of the 30 volunteers the pattern of CSF flow was normal according to conventional criteria. In these subjects the radioactivity was symmetrically located over the parietal cortex 24 h after the injection and no intraventricular activity could be recorded. In 11 (41%) of the subjects, radioactivity could be observed in the lateral ventricles 6 h after injection. One of these subjects had a reflux of radioactivity into the lateral ventricles. The intraventricular radioactivity persisted for at least 24 h. This subject also had signs of obstruction of CSF flow over the convexities. Asymmetric distribution of radioactivity within the CSF spaces was observed in the images obtained after 6 but not 24 h in two cases. One of those also demonstrated transient intraventricular radioactivity. The results of the computed tomography were interpreted to be normal in 19 (63%) of the 30 volunteers. One subject had an asymmetric ventricular system. The CT scans of six subjects (20%) differed considerably from the others as they displayed wide cortical or vermian sulci at the borderline of normal variations. The case with the pathological RC belonged to the group of subjects who had wide sulci.(ABSTRACT TRUNCATED AT 250 WORDS)
Citalopram is a bicyclic phtalane derivative. In animal experiments, citalopram has been demonstr... more 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. MO-PEG 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.
Cognitive deficits represent a significant characteristic of schizophrenia. However, a majority o... more 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 Egger's 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.
Tyrosine supplementation in humans has been shown to improve cognitive functioning. Several studi... more 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. 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. 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. 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.
The aim of the present study was to investigate socioeconomic and demographic determinants of dir... more The aim of the present study was to investigate socioeconomic and demographic determinants of direct costs for psychiatric disorders in Sweden. The cost categories were inpatient and outpatient costs, and costs for psychopharmacological drugs. Two consecutive years, 2001 and 2002, were chosen as the study period. The study included all costs for admissions, visits and prescribed drugs for adults aged > or = 18 years in 2001 and 2002 in Sweden. These costs were aggregated and analysed at the county level. A multiple linear regression analysis was fitted to the data, and independent variables (i.e. predictors) were chosen on the basis of previous studies. All cost types (e.g. total, inpatient, outpatient and drug costs) were analysed separately in different models. Large variations in total direct psychiatric costs were found between county councils (for example, the total costs varied between euro112 and euro195 per capita in 2001). The results indicate that psychiatric outpatient care is less utilized in rural than in urban areas, and drugs are more often prescribed in rural areas than in urban areas. Areas with a high proportion of women and people aged 65 years and over are strong predictors of mental healthcare costs, i.e. variables showing that the higher the proportion, the lower the direct costs. Factors such as urbanization, gender, age and number of immigrants are reasons for differences in psychiatric direct costs. On the basis of these findings, it seems plausible to conclude that women, older patients and immigrants may benefit from specialized psychiatry, but that such healthcare does not seem to be provided in all regions.
To further evaluate the controversial putative association between a Ser9Gly variant in the first... more To further evaluate the controversial putative association between a Ser9Gly variant in the first exon of the dopamine D3 receptor gene (DRD3) and schizophrenia. Swedish patients with schizophrenia ( n=156) and control subjects ( n=463) were assessed for the DRD3 Ser9Gly variant. Meta-analyses including previous and the present Swedish case-control results were performed. No significant difference between the Swedish patients and controls were found, but there was an association between DRD3 Ser9Gly Ser/Ser and homozygous genotypes and response to anti-psychotic drugs. This finding was supported by an incomplete meta-analysis. In a meta-analysis of all case-control studies comprising 8761 subjects the association between DRD3 Ser9Gly homozygosity and schizophrenia ( =4.96, degree of freedom=1, p <0.05, odds ratio=1.10, 95% confidence interval=1.01-1.20) persisted. However, the previously proposed association between the Ser/Ser genotype and schizophrenia was not significant (chi2 =2.71, degree of freedom=1, p>0.05, odds ratio=1.08, 95% confidence interval=0.99-1.17). Whereas the present Swedish case-control analysis did not yield any evidence for association with the diagnosis, the present meta-analysis suggests that the DRD3 gene confer susceptibility to schizophrenia. Reasons for the discrepancies between prior studies are discussed.
Disturbances in catecholamine transmission have been implicated in schizophrenia. Dopamine beta-h... more Disturbances in catecholamine transmission have been implicated in schizophrenia. Dopamine beta-hydroxylase catalyses the conversion of dopamine to norepinephrine in noradrenergic cells. We attempted to investigate a putative functional promoter polymorphism in the dopamine beta-hydroxylase gene (DBH) for association with schizophrenia. Unrelated schizophrenic patients (n=155) and control subjects (n=436) were analysed with regard to the DBH -1021 C/T variant. No significant allele or genotype differences were found. The present results do not support a major involvement of the DBH gene in schizophrenia in the Swedish population investigated.
To identify clinical cues indicative of depression in medical records of cases in primary care wi... more To identify clinical cues indicative of depression in medical records of cases in primary care with undetected depression. Depressive disorders are common; the lifetime risk for men and women is 27% and 45%, respectively. Despite effective treatment methods such as antidepressants and cognitive behavioural therapy, depression often remains undiscovered in primary care, with great implications both on the individual and societal level. Clinical cues indicating depression were sought in medical records the year before an opportunistic screening for depression in primary care. In a previous study of 221 patients in the waiting room of a primary care centre during 10 randomly selected days, 45 (20%) showed signs of depression (MADRS-S ⩾ 12) and 60% of these were verified as having depressive disorders (Prime-MD). These 45 patients constitute the cases in the present study. Age- and gender-matched controls were selected among those who scored below the chosen cut-off level. Seventeen (38%) of the 45 cases compared with eight (18%) of the 45 controls had one or more cues [odds ratio (OR) 2.81; 95% confidence interval (CI): 1.06-7.43]. Sleep disturbance showed the greatest difference between cases and controls (OR 4.53; 95% CI: 1.17-17.55). A significant relationship was found between severity of depression, frequency of cues and lower functional level. Cues were twice as common in patients with undetected depression and their functional level was lower. A two-stage procedure, screening and a structured diagnostic interview, is recommended when sleep disturbances and lowered function are present.
Human fibroblast cells are an advantageous model to study the transport of amino acids across cel... more 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.
Radiological assessments of patients with symptoms of impaired cerebrospinal fluid (CSF) circulat... more Radiological assessments of patients with symptoms of impaired cerebrospinal fluid (CSF) circulation are usually based on observations of anatomical and functional alterations using computed tomography (CT) and radionuclide cisternography (RC). In order to define criteria of normality for these two techniques, 30 healthy volunteers have been studied. In the studies of CSF flow the radiopharmaceutical 99mTc-DTPA was used and single photon emission computed tomography (SPECT) was performed as a complement to planar scintigraphy. In 16 of the 30 volunteers the pattern of CSF flow was normal according to conventional criteria. In these subjects the radioactivity was symmetrically located over the parietal cortex 24 h after the injection and no intraventricular activity could be recorded. In 11 (41%) of the subjects, radioactivity could be observed in the lateral ventricles 6 h after injection. One of these subjects had a reflux of radioactivity into the lateral ventricles. The intraventricular radioactivity persisted for at least 24 h. This subject also had signs of obstruction of CSF flow over the convexities. Asymmetric distribution of radioactivity within the CSF spaces was observed in the images obtained after 6 but not 24 h in two cases. One of those also demonstrated transient intraventricular radioactivity. The results of the computed tomography were interpreted to be normal in 19 (63%) of the 30 volunteers. One subject had an asymmetric ventricular system. The CT scans of six subjects (20%) differed considerably from the others as they displayed wide cortical or vermian sulci at the borderline of normal variations. The case with the pathological RC belonged to the group of subjects who had wide sulci.(ABSTRACT TRUNCATED AT 250 WORDS)
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