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Biomedical subjects

W F Gattaz

Publications and source records attributed to W F Gattaz.

At least 37 records · Page 2Linked to original sources
PubMed1998

Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology -- a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist. The Amisulpride Study Group.

The benzamide amisulpride (ASP) is a selective D2-like dopamine antagonist, while flupentixol (FPX), a thioxanthene, blocks D2-like, D1-like and 5-HT2 receptors. To evaluate efficacy and safety of ASP and to investigate the importance of an additional D1-like antagonism for antipsychotic effects and extrapyramidal tolerability, a randomized double-blind multi- center study versus FPX as reference drug was performed for 6 weeks in 132 patients suffering from acute schizophrenia (DSM-III-R) with predominant positive symptomatology. Doses were initially fixed (ASP: 1000 mg/day; FPX: 25 mg/day) but could be reduced by 40% in case of side effects (mean daily doses: ASP: 956 mg; FPX: 22.6 mg). Intention-to-treat evaluation demonstrated significant improvement under both medications. The difference between the mean BPRS decreases of both treatment groups was 5.6 points (95% CI: 0.55; 10.65) in favour of ASP. According to CGI, 62% of patients in either drug group were treatment responders. ANCOVA analysis showed that reductions of BPRS (ASP: -42%; FPX: -32%) and SAPS (ASP: -78%; FPX: -65%) were more pronounced under ASP. Due to adverse events, significantly fewer ASP patients (6%) were withdrawn from the study (FPX: 18%). Extrapyramidal tolerability was better in the ASP group, as demonstrated by smaller increases in the Simpson-Angus Scale, the AIMS, and the Barnes Akathisia Scale in ANCOVA analyses with dosage as covariate. ASP appears to be as effective as FPX with regard to antipsychotic effects on positive schizophrenic symptomatology, while extrapyramidal tolerability is better. These conclusions have to be drawn cautiously, as dosage effects on outcome parameters cannot be entirely ruled out. The present results question the notion that additional blockade of D1-like receptors may be necessary to achieve sufficient antipsychotic effects or to improve extrapyramidal tolerability.

Adult↗
PubMed1998

Causes and consequences of the gender difference in age at onset of schizophrenia.

The ABC (age, beginning, course) schizophrenia study was commenced in 1987 to generate and test hypotheses about pathogenic aspects of schizophrenia. One of the main branches of the study focused on how gender influences the age distribution of onset, symptomatology, illness behavior, and early course in schizophrenia. Proceeding from one of the rare, strikingly deviating, consistent findings--the gender difference in age at first admission--we launched a systematic search for explanations by generating and testing hypotheses in a series of substudies. We moved from the epidemiological to the neurobiological and finally to the clinical level. The present article is an attempt to provide a brief overview of the individual stages of the ABC study and the different levels of investigation involved in formulating and testing the estrogen hypothesis in animal experiments and in demonstrating its applicability to human schizophrenia. From these results, three hypotheses were formulated and tested on data from an ABC study sample of 232 first-episode cases of schizophrenia. The analyses described here represent the latest stages of the ABC study.

Adolescent↗
PubMed1998

Effects of beta-amyloid peptides on the fluidity of membranes from frontal and parietal lobes of human brain. High potencies of A beta 1-42 and A beta 1-43.

beta-amyloid peptide (A beta) and several A beta-fragments decrease the fluidity of human cortex membranes in a concentration dependent fashion. The effect of A beta on membrane fluidity increases with peptide length, is most pronounced for A beta 1-43 and can be seen at concentrations as low as 100 nmol/l. While the fragment A beta 25-35 is active, scrambled peptide (A beta 35-25) when investigated under similar conditions shows no effects on membrane fluidity. The effect of A beta peptides on fluidity of the phospholipid bilayer is more pronounced in the hydrocarbon core (labeled with the fluorescence probe 1,6-diphenylhexa-1,3,5-triene) than in the region of the hydrophilic heads (labeled with the fluorescence probe 1-[4'-(trimethylamino)phenyl]-6-phenylhexa-1,3,5-triene). It is suggested that the effect of A beta on neuronal membranes is probably a major initial mechanism in a cascade of events finally leading to neurotoxicity and cell death in Alzheimer's disease.

Alzheimer Disease↗
PubMed1996

Decreased phospholipase A2 activity in the brain and in platelets of patients with Alzheimer's disease.

Phospholipase A2 (PLA2) is a key enzyme in the metabolism of membrane phospholipids. PLA2 influences the processing and secretion of the amyloid precursor protein, which give rise to the beta-amyloid peptide, the major component of the amyloid plaque in Alzheimer's disease (AD). We investigated the PLA2 activity in two samples: in post-mortem brains from 23 patients with AD and 20 non-demented elderly controls, and platelets from 16 patients with a diagnosis of probable AD, 13 healthy controls and 14 elderly patients with a major depression. In AD brains PLA2 activity was significantly decreased in the parietal, and to a lesser degree in the frontal, cortex. Lower PLA2 activity correlated significantly with an earlier onset of the disease, an earlier age at death and higher counts of neurofibrillary tangles and senile plaques. In platelets PLA2 activity was also significantly reduced in the AD group as compared with healthy and depressed controls. The reduction of the enzyme activity in platelets correlated with an early disease onset and with the severity of cognitive impairment, indicating a relationship between abnormally low PLA2 activity and a more severe form of the illness. The present results provide new evidence for a disordered phospholipid metabolism in AD brains and suggest that reduced PLA2 activity may contribute to the production of amyloidogenic peptides in the disease. Further studies are needed to examine whether PLA2 activity in platelets may be useful as a peripheral marker for a subgroup of patients with AD.

Age of Onset↗
PubMed1996

Digital movement analysis, a new objective method of measuring tardive dyskinesia and drug-induced parkinsonian tremor: acceptability, reliability and validity.

Digital movement analysis (DMA) is a new instrumental approach to assessing oral tardive dyskinesia (TD) by means of digital image processing of a video signal, tracking five paper dots placed around the patient's mouth. A total of 40 schizophrenic patients, 30 with and 10 without TD, were examined twice (with a 3-month interval) with this new device. The patients were further examined with two TD rating scales: the St. Hans Rating Scale for extrapyramidal syndromes (SHRS) and the Abnormal Involuntary Movement Scale (AIMS). The schizophrenic patients accepted the instrumental assessment without any anxiety or resistance. The internal reliability of the apparatus was high, with correlation coefficients of 0.80-0.99. The DMA TD values correlated with the SHRS and AIMS scores with correlation coefficients of 0.48-0.73 indicating an acceptable, although not strong, concurrent validity. Fluctuations occurred from the first to the second examination independent of medication. For these fluctuations no correlation was found between DMA values and rating scores. Finally, the DMA device was able to detect perioral tremor as a sign of parkinsonism. It has been concluded that DMA is a useful supplement to classical TD rating, although further validity evaluation is warranted.

Adult↗
PubMed1996

Phospholipase A2 and the hypofrontality hypothesis of schizophrenia.

Phospholipase A2 (PLA2) catalyzes the hydrolysis of membrane phospholipids to release cytotoxic products such as lysophosphatidylcholine. In schizophrenia increased PLA2 activity and an accelerated breakdown of membrane phospholipids have been reported. In neuronal do membranes PLA2 modulates dopamine (DA) release and DA receptor sensitivity. Using two different animal models we show inhibition of dopaminergic activity in vivo by intracerebral PLA2 application. (1) Unilateral stereotaxic injection of PLA2 into the substantia nigra pars compacta causes an apomorphine-induced ipsilateral rotational asymmetry. (2) Intracerebroventricular PLA2 application reduces apomorphine-induced locomotion. NMR spectroscopy studies show a disordered phospholipid metabolism in the prefrontal cortex (PFC) of schizophrenics. The hypofrontality hypothesis of schizophrenia postulates hypodopaminergic activity in the prefrontal cortex. We speculate that increased PLA2 activity in the PFC of schizophrenics might be related to both abnormalities and could thus contribute to hypofrontality in schizophrenia.

Animals↗
PubMed1996

[Relevance of metabolism of membrane phospholipids for Alzheimer dementia].

We found a decreased activity of the enzyme phospholipase A2 (PLA2) in brain tissue from 23 patients with Alzheimer's disease (AD) compared to 20 non-demented controls. The decrement was more pronounced in patients with an early onset of disease and correlated significantly with higher counts of senile plaques and neurofibrillary tangles. Decreased PLA2 activity may inhibit the secretion of the amyloid precursor protein (APP) and thus contribute to the formation of the beta-amyloid peptide, the major component of the amyloid plaque in AD. Because PLA2 activity is under genetic control, it is conceivable that the enzyme activity in the brain is related to the activity in blood cells. To test this assumption we investigated PLA2 in platelet membranes from AD patients compared to healthy and psychiatric controls. Platelets are interesting peripheral models in AD research, because they contain and secrete APP. We determined the platelet PLA2 activity in 16 patients with a "probable" AD (NINCDS-ADRDA criteria) as compared to 13 healthy controls and to 14 psychiatric patients with a major depression. There were no significant differences between the three groups regarding age and sex distribution. In the AD patients the cognitive performance was assessed with the CAMCOG and the Mini Mental State Exam (MMSE). The radioenzymatic assay for the determination of PLA2 activity is described elsewhere. Platelet PLA2 activity was significantly reduced in AD patients as compared to healthy (p < 0.03) and to psychiatric controls (p < 0.002). The reduction of the enzyme activity correlated with an early onset of the disease (rs = .43, p < 0.10) and with the cognitive impairment in the CAMCOG (rs = .55, p < 0.05). AD patients with a MMSE-score lower than 10 (median) showed significantly lower PLA2 activity (11.8 +/- 3.1) than patients with MMSE-score higher than 10 (16.2 +/- 4.6, p < 0.05). These findings in platelets are in line with our previous results in brain tissue. In both studies decreased PLA2 activity was related to a more severe form of AD (early onset, more cognitive impairment and higher number of plaques and tangles). Moreover, reduced platelet PLA2 activity was specific for AD as compared to age-matched psychiatric controls. Further studies should clarify whether PLA2 activity in platelets could be useful as a peripheral marker for a subgroup of AD.

Aged↗
PubMed1995

Intracerebroventricular injection of phospholipase A2 inhibits apomorphine-induced locomotion in rats.

Phospholipase A2 (PLA2) is a key enzyme in phospholipid metabolism. In neurons, membrane-bound PLA2 plays an essential role in signal transduction by affecting neurotransmitter release and receptor sensitivity. There are some reports of increased PLA2 activity in schizophrenia. We investigated the effects of intracerebroventricular (i.c.v.) injections of PLA2 on dopamine-mediated behavior in rats. Ten days after i.c.v. injection, PLA2 significantly inhibited apomorphine-induced locomotion as compared with i.c.v. saline injections. The inhibition of apomorphine-induced locomotion by PLA2 was reversible within 4 weeks after stereotaxic surgery. These findings suggest a functional inhibition of dopaminergic postsynaptic receptors by PLA2. Accelerated phospholipid metabolism and reduced dopaminergic activity in the prefrontal cortex have been postulated to play a role in schizophrenia. Increased PLA2 activity may be related to both abnormalities and could thus play a role in the pathophysiology of schizophrenia.

Animals↗
PubMed1995

Decreased phospholipase A2 activity in Alzheimer brains.

Phospholipase A2 (PLA2) is a key-enzyme in the metabolism of membrane phospholipids. In cholinergic neurons PLA2 controls the physico-chemical properties of neuronal membranes as well as the breakdown of phosphatidylcholine to produce choline for acetylcholine synthesis. Moreover PLA2 influences the processing and secretion of the amyloid precursor protein, which gives rise to the beta-amyloid peptide, the major component of the amyloid plaque in Alzheimer's disease (AD). In the present study PLA2 activity was investigated in post-mortem brains from 23 patients with AD and 20 nondemented elderly controls. In AD brains PLA2 activity was significantly decreased in the parietal and to a lesser degree in the frontal cortex. Lower PLA2 activity correlated significantly with an earlier onset of the disease, higher counts of neurofibrillary tangles and senile plaques and an earlier age at death, indicating a relationship between abnormally low PLA2 activity and a more severe form of the illness. The present results provide new evidence for a disordered phospholipid metabolism in AD brains and suggest that reduced PLA2 activity may contribute to the cholinergic deficit and to the production of amyloidogenic peptides in the disease.

Aged↗
PubMed1995

Cardiovascular effects of fluvoxamine and maprotiline in depressed patients.

In the choice of an antidepressant drug the clinician must often consider the presence of a cardiovascular comorbidity in depressed patients. In the present study the cardiovascular effects of fluvoxamine and maprotiline were compared in a double-blind trial in which the quantitative changes in ECGs were assessed before and during a 3-week treatment. A total of 33 patients (mean age 44 years; range 20-65 years) with major depressive disorder (RDC) who were free from clinically relevant organic diseases were investigated. After a 7-day wash-out period, a 3 week treatment phase was started with 200 mg daily of either fluvoxamine (n = 18) or maprotiline (n = 15). On days 0, 7, 14 and 21 a 12-lead standard ECG was performed and the drug plasma levels were determined. All ECGs were analysed in a blind fashion by an internist. Maprotiline caused a significant prolongation of the PR interval (P < 0.001) and of the QRS interval (P < 0.01) was well as an increase in heart rate (P < 0.001). The QTc interval was only tendentially prolonged (P < 0.10) and the P-wave duration and T-wave amplitude were not affected by maprotiline. No significant changes in ECG parameters were observed during treatment with fluvoxamine; and there was a nonsignificant trend (P < 0.10) for a lower heart rate during treatment. Blood pressure was not affected by treatment with either antidepressant. In both groups no significant correlations were found between ECG findings and the plasma levels of the drugs. Our results confirm that fluvoxamine in therapeutic dose causes no alteration in surface ECG regarding cardiac conduction and repolarization. Conversely, maprotiline caused a significant prolongation of atrioventricular and intraventricular conduction and a rise in heart rate. Although these effects were not clinically relevant in our sample of patients without overt heart disease, they should be taken into account when treating depressed patients with concomitant cardiac disease.

Adult↗
PubMed1995

Intracerebral injection of phospholipase A2 inhibits dopamine-mediated behavior in rats: possible implications for schizophrenia.

Phospholipase A2 (PLA2) is a key enzyme in the phospholipid metabolism. In the CNS intracellular PLA2 plays an essential role in signal transduction by affecting both dopamine (DA) release and DA-receptor sensitivity. In schizophrenia a disordered phospholipid metabolism and increased activity of PLA2 have been reported. In this study we investigated the effects of intracerebral PLA2 injections on dopaminergic neurotransmission in rats using Ungerstedt's model of rotational behavior. Circling behavior induced by the DA agonist apomorphine after unilateral PLA2 injections into the substantia nigra pars compacta was recorded. Seven and 21 days after intranigral PLA2 injection, apomorphine induced an ipsilateral rotation indicating a long-lasting inhibition of ipsilateral nigrostriatal dopaminergic pathway by PLA2 application. In schizophrenia a reduced dopaminergic activity in the frontal cortex has been hypothesized. Recent spectroscopy studies reported on an accelerated break-down of membrane phospholipids in the frontal cortex from schizophrenics. The present findings suggest that increased PLA2 activity in schizophrenia could accelerate the breakdown of membrane phospholipids and thus contribute to a hypodopaminergy in the frontal cortex of schizophrenic patients.

Animals↗
PubMed1995

Oral tardive dyskinesia: validation of a measuring device using digital image processing.

The present study was performed to investigate the reliability and validity of a new device for the assessment of oral dyskinesias by means of digital image processing. Twenty schizophrenic patients with tardive dyskinesia (TD) and ten healthy controls were studied. In patients instrumental scores were compared to different clinical rating scale scores. Measurements were repeated after 2 weeks under the same circumstances to assess test-retest stability. Instrumental scores discriminated well between normal subjects and dyskinetic patients and correlated significantly with clinical ratings (r = 0.63). The test-retest correlations showed a correspondence not larger than 40%, detecting thus the fluctuation of the TD intensity over time. These results suggest that our device is a reliable and easy to handle technique for the assessment of TD. Furthermore, the ability of the device to analyze the frequency distribution of movements makes it a useful tool for the quantitative and qualitative analysis of TD.

Adult↗
PubMed1995

Increased platelet phospholipase A2 activity in schizophrenia.

The intracellular enzyme phospholipase A2 (PLA2) plays an essential role in the breakdown of membrane phospholipids, which regulate the physicochemical properties of the cell membrane. In the brain PLA2 has been reported to influence receptor function and signal transduction. Regarding dopaminergic neurons, data from animals experiments and from binding studies suggest that PLA2 activation reduces dopaminergic neurotransmission. In the present study we investigated intracellular PLA2 in platelets from 31 DSM-III-R paranoid schizophrenic patients (15 neuroleptic-naive) compared to 31 healthy individuals and to 31 non-schizophrenic psychiatric controls, both matched to the schizophrenics by age and sex. Platelet PLA2 activity was significantly increased in schizophrenics as compared to healthy and to psychiatric controls. Neuroleptic treatment reduced significantly the enzyme activity. Our findings in platelets suggest an accelerated breakdown of membrane phospholipids in schizophrenia. An accelerated phospholipid breakdown has also been reported in the frontal cortex from schizophrenic patients. Further studies should clarify whether increased PLA2 in the brain, as observed in platelets, could contribute to a frontal dysfunction in schizophrenia.

Adult↗
PubMed1995

Moclobemide versus fluoxetine in the treatment of inpatients with major depression.

Seventy inpatients with a DSM-III-R major depression were included in a double-blind, randomized, clinical trial to compare the efficacy and tolerability of moclobemide versus fluoxetine. After a 3-day placebo run-in phase, treatments were administered for 4 weeks in daily doses of between 300 and 600 mg of moclobemide or 20 to 40 mg of fluoxetine. Efficacy was measured by the Hamilton Rating Scale for Depression (HAM-D), Clinical Global Impression, and subjective mood ratings (45-item self-rating scale). Fifty-three patients (mean age, 40 years; 22 men, 31 women) completed the 4-week treatment. Changes between end of treatment and baseline did not differ between both study drugs. The HAM-D responder rate (50% improvement from baseline) was 59% in the moclobemide group and 58% in the fluoxetine group after 4 weeks. Moclobemide, however, acted therapeutically faster than fluoxetine. After 1 week of treatment, the HAM-D scores were significantly lower in patients on moclobemide than in those on fluoxetine (p < 0.005). The earlier efficacy of moclobemide after 1 week was also detected by the patients' subjective mood ratings (p < 0.02). There were no differences between moclobemide and fluoxetine regarding tolerability ratings. These data suggest that both agents have a similar efficacy and tolerability but that moclobemide has an earlier onset of antidepressive action.

Adolescent↗
PubMed1994

Effects of zotepine, haloperidol and clozapine on MK-801-induced stereotypy and locomotion in rats.

In the present study we compared the effects of the atypical neuroleptic zotepine to haloperidol and clozapine on stereotypies and locomotion induced in rats by the N-methyl-D-aspartate (NMDA) antagonist MK-801. Zotepine caused a dose-dependent reduction of MK-801-induced stereotypies and locomotion. Zotepine at a dosis of 2.5 mg/kg body weight showed a similar effect to 0.25 mg/kg haloperidol in reducing stereotypies and locomotion. Clozapine (5.0 mg/kg) reduced significantly locomotion and non-significantly stereotypies. These results add support to the assumption that MK-801-induced behavior provides an adequate animal model to test the potential efficacy of typical and atypical neuroleptics in the treatment of psychoses.

Animals↗