M. Riedel

Effects of treatment with the atypical neuroleptic quetiapine on working memory function: a functional MRI follow-up investigation

BackgroundWorking memory as a part of higher-order executive functions is defined by the parallel storage and processing of information. Recent functional fMRI studies have revealed a functional, interregional disintegration of a neuronal network connecting cortical, subcortical and cerebellar regions in schizophrenic patients (SZ). Cognitive impairment in working memory is a core psychopathological correlate of schizophrenic symptoms. Atypical neuroleptics such as quetiapine have shown good efficacy in treating positive and negative symptoms. The presented study evaluated the impact of a neuroleptic steady state treatment with quetiapine on the altered working memory activation patterns in schizophrenia.MethodsPatients were examined by fMRI at baseline and after 12xa0weeks of steady state treatment with quetiapine. Matched healthy controls (HC) underwent baseline examination. In the scanner, stimuli were presented in a 2-back and 0-back condition of a working memory (wm) paradigm, whereby a degraded and a non-degraded version were used each time. Additionally, behavioural responses (reaction time to target stimuli and error ratio) were measured.ResultsAt baseline, healthy controls revealed increased activity in the frontal lobe, especially in regions of the prefrontal cortex. Compared to HC, SZ showed hypoactivation in the right dorsolateral prefrontal cortex (DLPFC) and the ventrolateral prefrontal cortex (VLPFC) bilaterally for the 2-back condition. In the 2-back degraded condition there was a hypoactivation in both, the right DLPFC and the VLPFC. Additionally, patients showed bilaterally decreased activation in the basalganglia in the 2-back and in the right caudatus in the 2-back degraded condition compared to healthy controls. After treatment with quetiapine, patients activations patterns were increased. The pre–post comparison of the 2-back condition revealed a significant increase of activation in the left VLPFC at a significance level of 0.001 (uncorrected). The 2-back degraded condition led to a significant activation pattern in the lingual gyrus and the right precuneus. In both wm conditions, at baseline there were no differences in reaction time but only a worse performance in SZ. After treatment, behavioural measurement of responses, including reaction time and performance, showed slight improvements in SZ, although these did not reach statistical significance.ConclusionsThe neuronal networks underlying working memory are clearly altered in schizophrenia. After 12xa0weeks of treatment with quetiapine monotherapy, patients showed significant clinical improvement and revealed increased BOLD activity in the VLPFC during a working memory task, although there was no improvement of cognitive performance.

Soluble IL-6 receptors in the serum and cerebrospinal fluid of paranoid schizophrenic patients

Soluble Interleukin-6 receptor (sIL-6R) levels are strongly related to the levels of Interleukin-6 (IL-6), and sIL-6Rs increase the immune activating properties of IL-6. We estimated sIL-6R serum levels in 25 schizophrenic patients and 25 healthy controls. In the patients, SIL-6R-CSF levels were also measured. The psychopathology was rated according to the AMDP system. We found a significant correlation between serum and cerebrospinal fluid (CSF) levels of sIL-6R, suggesting that serum levels may be a meaningful marker for the central action of sIL-6R. Moreover, significant correlations between the paranoid-hallucinatory syndrome and sIL-6R levels both in serum and CSF were observed. This finding suggests that IL-6 plays a role in the paranoid-hallucinatory symptomatology in schizophrenia. This can be understood regarding the influence of IL-6 to the catecholaminergic neurotransmission. The downregulating effects of neuroleptic treatment to sIL-6R demonstrate that the sIL-6R levels are decreased in the whole group of schizophrenic patients compared to controls.

Autoantibodies against 60-kDa heat shock protein in schizophrenia.

Abstract Immunological abnormalities in schizophrenic patients have been reported for many years. However, the question of whether these parameters are involved in the pathophysiology of the disorder or represent treatment effects is still not answered. We investigated a combination of humoral and soluble immune parameters in 30 unmedicated schizophrenic patients before and during antipsychotic treatment and in 31 healthy controls. The aim of our study was to unravel an underlying immune process, to elucidate the influence of neuroleptic treatment and to identify a subgroup of schizophrenics. Antibodies against human 60-kDa heat-shock protein (HSP60), serum levels of soluble ICAM-1 and IL-2R were determined and correlated with parameters of blood–brain barrier and of psychopathology. In 10% of the drug-free but in 20% of the medicated schizophrenics, especially in females, we observed immunoreactivity against HSP60, high levels of IgG in CSF and a blood–brain barrier impairment. The high HSP antibody titres correlated with high levels of sIL-2R and sICAM-1. Only one of the controls showed antibodies against HSP60. Our results suggest that the observed immunological alterations are more pronounced during neuroleptic treatment than in the drug-free state. Whether or not this differential response to treatment with altered antibody production represents a subgroup of patients has yet to be determined.

How representative of everyday clinical populations are schizophrenia patients enrolled in clinical trials

AbstractIntroductionThere has been considerablendiscussion whether clinical trials accurately depictneveryday practice. Restrictive inclusion/exclusion criteria,nethical considerations, differences in the severity ofnpsychopathology between clinical and trial patients, ornsafety issues may bias results, which in turn may rathernrepresent outcome for the “ideal” than for the “average”npatient. Therefore, translation into psychiatric practicenmay be difficult.MethodsA retrospective case–controlnstudy was performed. Schizophrenia inpatients at thenLMU Department of Psychiatry, Munich, Germany, whonhad participated in clinical trials were compared to regularnpatients serving as controls. Probands and controlsnwere matched by DSM–IV diagnosis, gender and age.nThe AMDP module, CGI and GAF were used to comparenpsychopathology. In addition, charts were reviewed fornmedication dosages, concurrent medical and neurologicalnillness, and clinical history such as age of onset ornfamily history.ResultsA total of 200 probands (100/100)nwere enrolled in the study. With respect to psychopathology,nformally thought disordered or suicidalnpatients were significantly less likely to be study participantsn(n = 3) than controls (n = 22; p ≤ 0.05). Similarly,nnegative schizophrenia symptoms were significantlynless often present in study participants (n = 17) than inncontrols (n = 38; p ≤ 0.05). Study participants were alsonmedically and neurologically healthier than controls.n(p = 0.05 respectively). No differences in overall illnessnseverity as depicted by CGI and GAF were observed.ConclusionWe found the patients included in our clinicalntrials representative of the patient encountered innroutine clinical practice. Adherence to inclusion and exclusionncriteria prevents inclusion of severely ill (e. g.nsuicidal) patients requiring a more intensive treatmentnsetting. Illness severity was found to be similar in trialnparticipants and controls, and indicates an overall comparablynsevere psychopathology. The more chronic,nrather treatment refractory patients were also not reflectednin the trial participant pool; this population maynarguably not represent the average clinical patient either.nA more careful administration of antipsychoticnmedication was found in trial participants and may effectivelynbe considered “good clinical practice”.

The Munich 15-year follow-up study (MUFUSSAD) on first-hospitalized patients with schizophrenic or affective disorders: Assessing courses, types and time stability of diagnostic classification

OBJECTIVEnIn the context of the development of DSM-V and ICD-11 it appears to be useful to get further data on the validity of the diagnostic differentiation between schizophrenic and affective disorders. This study investigated the relevance of the main diagnostic groups schizophrenia, schizoaffective psychosis and affective disorder in the context of different diagnostic systems (ICD-9, ICD-10, DSM -IV), assessing their time stability, long-term courses, types and functional outcome.nnnMETHODSnA total of 323 first hospitalized inpatients of the Psychiatric Department of the University Munich were recruited at index time. The full follow-up evaluation including standardized assessment procedures could be performed in 197 patients.nnnRESULTSnThe re-diagnosis of the patients disorders shows that with the transition from ICD-9 to ICD-10 or DSM-IV, the group of affective disorders increased numerically while the diagnostic groups of schizophrenia and schizoaffective disorders decreased in size. The structured clinical interview for DSM-IV (SCID) analysis showed that altogether ICD-10 and DSM-IV had a relatively high diagnostic stability. Of the patients with an ICD-10 diagnosis of schizophrenia, 57% had a chronic course; 61% of the patients with a DSM-IV diagnosis of schizophrenia. Patients with affective disorders, according either to ICD-10 or DSM-IV, had in more than 90% of the cases an episodic-remitting course. In terms of prediction of long-term outcome regarding the differentiation between chronic and non-chronic course, the ICD-10 diagnoses did give a slightly better predictive result than a dimensional approach based on the key psychopathological syndrome scores.nnnCONCLUSIONSnThe differentiation between schizophrenic and affective disorders seems meaningful especially under predictive aspects. A dimensional syndromatological description does not exceed the predictive power of the investigated main diagnostic categories, but might increase the clinically relevant information.

Decreased Stnf-Ri in Migraine Patients?

Tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) have recently been found to have a pain-mediating function in addition to their immunological, proinflammatory function. According to the hypothesis of neurovascular inflammation in migraine, these two cytokines could contribute to migraine pain generation. We analysed IL-6 and its soluble receptors sIL-6R and sgp130 as well as TNF-α and its soluble receptor sTNF-RI in 27 migraine patients and eight headache-free controls. Migraine patients tended to have less sTNF-RI (794 ± 158 pg/ml) than controls (945 ± 137 pg/ml). No differences in cytokine concentrations were observed. If TNF-α plays a role in migraine physiopathology, migraine patients may lack sufficient antagonistic sTNF-RI to neutralize hyperalgesic TNF-α during a migraine attack.

Internally and externally guided voluntary saccades in unmedicated and medicated schizophrenic patients. Part I. Saccadic velocity

Abstract Saccadic eye movements were elicited in 30 schizophrenic patients before and in 17 of these 30 during antipsychotic treatment with neuroleptics, and compared with those of 12 age-matched controls under three different conditions: (a) the gap paradigm, which tests the visually triggered and visually guided saccades; (b) the anti-task paradigm, which tests the internally guided, visually triggered saccades; and (c) the memory paradigm, which tests the internally triggered and guided saccades. Eye movements were recorded by DC electro-oculography, and the peak eye velocities for the different saccades were calculated. We found that antipsychotic treatment with neuroleptics reduces the peak saccadic eye velocity. This effect is larger for internally guided saccades than for externally triggered and guided eye movements. The saccadic velocity of the unmedicated schizophrenic patients did not differ from that of the controls. Since patients with diseases of the basal ganglia primarily show abnormalities of the internally guided and triggered saccades, our findings indicate that neuroleptics influence the oculomotor loop through the basal ganglia and that this loop, by means of neuroleptic influence on the brainstem saccadic burst generator, also influences the peak velocity of the internally guided saccades. This contradicts the current idea of the role of the cortical input to the brainstem saccadic burst generator, which is thought to not be involved in the determination of saccadic velocity.

Different mechanisms of l-arginine induced dilation of brain arterioles in normotensive and hypertensive rats

We evaluated the response of pial arterioles to L-arginine in anesthetized normotensive rats and spontaneously hypertensive rats equipped with a closed cranial window. Topical application of 10(-6)-10(-4) mol/l L-arginine, which is known to be the endogenous substrate for the synthesis of nitric oxide, induced dose-dependent arteriolar vasodilation. The response was more pronounced in hypertensive than in normotensive rats (at the concentration of 10(-4) mol/l L-arginine: 18.3 +/- 3.3% vs. 6.7 +/- 1.7%, respectively, means +/- S.E.). The stereoisomer D-arginine had no effect in hypertensive rats. Topical application of the nitric oxide synthase inhibitor N-nitro-L-arginine converted L-arginine-induced dilation to constriction in normotensive and hypertensive rats. The cyclooxygenase inhibitor indomethacin (5 micrograms/ml cerebrospinal fluid) also blocked the dilation in both strains. Photochemical endothelial injury blocked L-arginine-induced dilation in normotensive rats, but only partly antagonized the response in hypertensive animals. Intravenous or topical pretreatment with the free radical scavenger superoxide dismutase significantly reduced the dilating response to 10(-4) mol/l L-arginine in hypertensive rats. Superoxide dismutase did not significantly change the response to L-arginine in normotensive animals. It is concluded that nitric oxid formation in the endothelium and liberation of cyclooxygenase products cause L-arginine-induced dilation in normotensive rats. While nitric oxide and cyclooxygenase products are also involved in L-arginine-induced dilation in spontaneously hypertensive rats, superoxide radicals contribute to the enhanced response in this strain. This mechanism appears to be specific for the hypertensive animals and is only partly dependent on an intact endothelium.

Dipole Localization of P300 and Normal Aging

At present, our understanding of how normal aging affects in vivo brain function is rudimentary. Therefore, the aim of the present study was to investigate age effects on auditory P300 topography. A recently developed dipole source model for P300 distinguishes overlapping P300 subcomponents and enhances reliability as well as validity of the measurement. 67 healthy subjects were examined using the P300 dipole model in addition to the scalp data measurement. The results show that P300 subcomponents reflect functionally different processes concerning age changes of P300 activities. Temporo-parietal P300 is smaller in older subjects, whereas frontal P300 is not attenuated. Age affected both P300 subcomponents latencies. Therefore, the functionally different alteration of P300 subcomponents might be the reason for P300 topography changes with the P300 maximum more frontally in older age.

Immunomodulatory Effects of Neuroleptics to the Cytokine System and the Cellular Immune System in Schizophrenia

The influence of an immune process on the pathogenesis of psychoses has been under discussion since the 1920s, when immune disturbances in schizophrenia, especially in catatonia, were reported by different authors (Bruce and Peebles, 1903; Dameshek, 1930; Lehmann-Facius, 1939).