Birte Y Glenthøj

Publications (17)81.43 Total impact

• Article: Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients.

  Ayna B Nejad, Kristoffer H Madsen, Bjørn H Ebdrup, Hartwig R Siebner, Hans Rasmussen, Bodil Aggernæs, Birte Y Glenthøj, William F C Baaré
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  ABSTRACT: Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p = 0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.
  The International Journal of Neuropsychopharmacology 11/2012; · 4.58 Impact Factor
• Article: Brain connectivity studies in schizophrenia: unravelling the effects of antipsychotics.

  Ayna B Nejad, Bjørn H Ebdrup, Birte Y Glenthøj, Hartwig R Siebner
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  ABSTRACT: Impaired brain connectivity is a hallmark of schizophrenia brain dysfunction. However, the effect of drug treatment and challenges on the dysconnectivity of functional networks in schizophrenia is an understudied area. In this review, we provide an overview of functional magnetic resonance imaging studies examining dysconnectivity in schizophrenia and discuss the few studies which have also attempted to probe connectivity changes with antipsychotic drug treatment. We conclude with a discussion of possible avenues for further investigation.
  Current Neuropharmacology 09/2012; 10(3):219-30. · 2.85 Impact Factor
• Article: Clonidine Normalizes Sensorimotor Gating Deficits in Patients With Schizophrenia on Stable Medication.

  Bob Oranje, Birte Y Glenthøj
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  ABSTRACT: Background : Cognitive deficits form core features in schizophrenia. Several studies have shown improvements in prefrontal cognitive function by α ( 2 ) -agonists in schizophrenia. In the present study, it was investigated whether clonidine (an α ( 2 ) -adrenoceptor agonist) could normalize sensorimotor gating deficits in schizophrenia. Methods : In a double blind, placebo controlled, randomized, yet balanced, cross-over experiment, 20 male schizophrenia patients on stable medication were assessed in an auditory prepulse inhibition (PPI), sensitization, and habituation of the startle reflex paradigm on 5 occasions: once after oral administration of placebo and after a single dose of 25, 50, 75, and 150 µg of clonidine. Their results were compared with 20 age- and gender-matched healthy volunteers, who received no treatment. Results : In the placebo treatment, patients showed deficient PPI and sensitization, yet normal habituation compared with the controls. Except the highest dose, all dosages of clonidine significantly increased percentage PPI in the patients compared with placebo, to such levels that it no longer differed significantly from the healthy controls. However, none of the dosages increased sensitization or influenced habituation. Conclusions : This is the first study to show that even a single low dose of clonidine added to the medical treatment of patients with schizophrenia who are clinically stable on their antipsychotic medication not only significantly ameliorates their PPI deficits, but also normalizes them. The results have a potentially high clinical relevance for the medical treatment of schizophrenia.
  Schizophrenia Bulletin 07/2012; · 8.80 Impact Factor
• Article: Relationship of frontal D2/3 binding potentials to cognition: a study of antipsychotic-naive schizophrenia patients.

  Birgitte Fagerlund, Lars H Pinborg, Erik Lykke Mortensen, Lars Friberg, William F C Baaré, Anders Gade, Claus Svarer, Birte Y Glenthøj
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  ABSTRACT: Studies of in vivo dopamine receptors in schizophrenia have mostly focused on D2 receptors in striatal areas or on D1 receptors in cortex. No previous study has examined the correlation between cortical dopamine D2/3 receptor binding potentials and cognition in schizophrenia patients. The objective was to examine this relation in the frontal cortex in first-episode, drug-naive schizophrenia patients. Based on preclinical and pharmacological evidence, we specifically expected to find a relation between D2/3 receptor binding potentials and set shifting. This was a cross-sectional, case-control study using single-photon emission computerized tomography with the D2/3-receptor ligand [123I]epidepride, co-registered with structural magnetic resonance imaging and correlated to cognitive measures. Participants were 24 antipsychotic-naive, first-episode schizophrenia patients and 20 healthy controls matched for gender and age. For patients, a significant linear correlation between D2/3 BPND and set shifting was found, while significant quadratic associations were observed for verbal fluency, planning and attention. For controls, the only significant association with D2/3 BPND was a quadratic partial correlation for set shifting. The main findings indicated a relation between D2/3 receptor binding in the frontal cortex and set shifting, planning and attention, but also support a differential involvement of cortical dopamine D2/3 receptor binding in at least some cognitive functions, perhaps particularly attention, in schizophrenia patients compared to healthy people. The results suggest that cortical D2/3 receptor function may be more involved in some cognitive functions (i.e. attention, fluency and planning) in patients with schizophrenia than in healthy people, suggesting that information processing in schizophrenia may be characterized by lower signal:noise ratios.
  The International Journal of Neuropsychopharmacology 02/2012; · 4.58 Impact Factor
• Article: The effect of acute exogenous melatonin on P50 suppression in healthy male volunteers stratified for low and high gating levels.

  Ebru Ucar, Emilia K Lehtinen, Birte Y Glenthøj, Bob Oranje
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  ABSTRACT: Sensory gating is frequently found to be disturbed in patients with schizophrenia. In addition, a disruption of the circadian rhythm together with a low nocturnal melatonin output is regularly found in these patients. Since there is some evidence that a brief period of sleep normalizes sensory gating in schizophrenia patients, it is conceivable that their disrupted melatonin level may contribute to the deficits in P50 suppression. In this initial study, the effects of acutely administered melatonin on sensory gating in healthy subjects were investigated. In a double-blind placebo-controlled crossover design, 21 healthy male volunteers were administered melatonin (4 mg) or placebo, after which they were tested in a P50 suppression paradigm. In the group as a whole, melatonin did not affect P50 suppression. However, melatonin increased the P50 ratio in the individuals with high baseline suppression. In contrast to what was expected, melatonin reduced P50 suppression, albeit only in those individuals with high baseline suppression. The current study does not support a beneficial effect of acute exposure to exogenous melatonin on sensory gating. Future research should focus on melatonin's ability to restore basic sleep rhythms and its subsequent effects on sensory gating, in both healthy volunteers and patients with schizophrenia.
  Journal of Psychopharmacology 02/2012; 26(8):1113-8. · 3.04 Impact Factor
• Article: P50 Suppression and its Neural Generators in Antipsychotic-Naive First-Episode Schizophrenia Before and After 6 Months of Quetiapine Treatment.

  Bob Oranje, Bodil Aggernaes, Hans Rasmussen, Bjorn H Ebdrup, Birte Y Glenthøj
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  ABSTRACT: Background: Numerous studies have demonstrated sensory gating deficits in schizophrenia. However, only a few longitudinal studies report on the effects of antipsychotic treatment on sensory gating deficits and their results are inconsistent. In the present study, P50 suppression and its neural generators were investigated in antipsychotic-naïve first-episode patients with schizophrenia before and after 6 months of treatment with quetiapine. Methods: Thirty-four antipsychotic-naïve first-episode schizophrenia patients and age and gender matched healthy controls were tested in an auditory sensory gating paradigm at baseline and after 6 months. During this period, the patients were treated with quetiapine, while controls received no treatment. Sixteen patients completed the study. Results: Patients showed significant reduced P50 suppression compared with controls at baseline but not at follow-up. Furthermore, a significant positive correlation between baseline P50 suppression and dose of quetiapine at follow-up was found. P50 suppression in patients receiving above median dosages of quetiapine increased significantly from baseline to follow-up. At baseline, a frontocentral source was significantly more active in patients than in controls at the time of the testing stimulus. Conclusions: The present findings suggest that P50 suppression deficits are already present at an early stage of schizophrenia. Furthermore, particularly those patients with more severe gating deficits appeared to need higher dosages of quetiapine, although their clinical symptoms did not seem to indicate this. Quetiapine treatment significantly improved these gating deficits. Furthermore, a frontocentral source in the brain appeared to be involved in the deficient P50 gating of the patients.
  Schizophrenia Bulletin 01/2012; · 8.80 Impact Factor
• Article: Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia.

  Ayna B Nejad, Bjørn H Ebdrup, Hartwig R Siebner, Hans Rasmussen, Bodil Aggernæs, Birte Y Glenthøj, William F C Baaré
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  ABSTRACT: Neuroimaging studies have shown abnormal task-related deactivations during working memory (WM) in schizophrenia patients with recent emphasis on brain regions within the default mode network. Using fMRI, we tested whether antipsychotic-naïve schizophrenia patients were impaired at deactivating brain regions that do not subserve WM. Twenty-three antipsychotic-naïve patients with first-episode schizophrenia and 35 healthy individuals underwent whole-brain 3T fMRI scans while performing a verbal N-back task including 0-back (no WM load), 1-back (low WM load), and 2-back (high WM load) conditions. Contrasting the 2-back and 0-back conditions revealed that patients deactivated default mode network regions to a similar degree as controls. However, patients were impaired in deactivating large bilateral clusters centred on the superior temporal gyrus with increasing WM load. These regions activated with the no WM load condition (0-back) in both groups. Because 0-back activation reflects verbal attention processes, patients' persistent activation in the 1-back and 2-back conditions may reflect an inability to shift cognitive strategy with onset of WM demands. Since patients were antipsychotic-naïve and task performance was equal to controls, we infer that this impaired temporoparietal deactivation may represent a primary dysfunction in schizophrenia.
  The World Journal of Biological Psychiatry 03/2011; 12(4):271-81. · 2.38 Impact Factor
• Article: Stability of prepulse inhibition and habituation of the startle reflex in schizophrenia: a 6-year follow-up study of initially antipsychotic-naive, first-episode schizophrenia patients.

  Trine Bjørg Hammer, Bob Oranje, Birgitte Fagerlund, Hannah Bro, Birte Y Glenthøj
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  ABSTRACT: Deficits in information processing appear to be core features in the pathogenesis of schizophrenia. Prepulse inhibition (PPI) and habituation of the startle reflex are operational measures of early information processing. Impaired PPI in schizophrenia has been replicated in many studies and is regarded as an endophenotype for schizophrenia. However, reports on the stability of PPI over a longer period of time are lacking, both for patients with schizophrenia and for healthy subjects. The current study examined 25 initially drug-naive, first-episode schizophrenia patients and 23 healthy matched controls. Three PPI measures [stimulus onset asynchrony (SOA) 30, 60, 120 ms] and habituation were assessed at baseline, and again after 6 yr. Sixteen patients and 17 healthy controls completed the study, and 13 patients and 17 healthy controls were included in the final analysis. The schizophrenia patients had PPI deficits compared to controls at baseline. After 6 yr, no significant group differences were found. PPI had increased significantly in the patients and had decreased significantly in controls. In addition, patients showed significantly less habituation than controls while habituation did not change in patients or controls. The present results show that PPI in drug-naive, first-episode schizophrenia patients can improve significantly over time. As PPI increased in patients over the same period that it decreased in controls, it is likely that the increase was caused by disease-related factors such as disease process, clinical state, or medication.
  The International Journal of Neuropsychopharmacology 02/2011; 14(7):913-25. · 4.58 Impact Factor
• Source

  Available from: Remko van Lutterveld

  Article: Increased psychophysiological parameters of attention in non-psychotic individuals with auditory verbal hallucinations.

  Remko van Lutterveld, Bob Oranje, Chantal Kemner, Lucija Abramovic, Anne E Willems, Marco P M Boks, Birte Y Glenthøj, René S Kahn, Iris E C Sommer
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  ABSTRACT: Schizophrenia is associated with aberrant event-related potentials (ERPs) such as reductions in P300, processing negativity and mismatch negativity amplitudes. These deficits may be related to the propensity of schizophrenia patients to experience auditory verbal hallucinations (AVH). However, AVH are part of extensive and variable symptomatology in schizophrenia. For this reason non-psychotic individuals with AVH as an isolated symptom provide an excellent opportunity to investigate this relationship. P300 waveforms, processing negativity and mismatch negativity were examined with an auditory oddball paradigm in 18 non-psychotic individuals with AVH and 18 controls. P300 amplitude was increased in the AVH group as compared to controls, reflecting superior effortful attention. A trend in the same direction was found for processing negativity. No significant differences were found for mismatch negativity. Contrary to our expectations, non-psychotic individuals with AVH show increased rather than decreased psychophysiological measures of effortful attention compared to healthy controls, refuting a pivotal role of decreased effortful attention in the pathophysiology of AVH.
  Biological Psychiatry 08/2010; 121(1-3):153-9. · 8.28 Impact Factor
• Article: [Cognitive deficits in schizophrenia and other psychotic disorders].

  Birgitte Fagerlund, Birte Y Glenthøj
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  ABSTRACT: Cognitive deficits are vulnerability indicators for psychotic disorders, particularly schizophrenia. The deficits remain stable throughout the illness in schizophrenia, but fluctuate with clinical state in other psychotic disorders. They are limiting factors for patients' prognoses and there is considerable incentive to develop treatments that can improve these deficits. The current brief review summarizes the relevance of cognitive deficits for the pathogenesis and prognosis of psychotic disorders, and identifies pertinent issues within the research field.
  Ugeskrift for laeger 12/2008; 170(46):3770-2.
• Article: [Neurobiological disturbances in schizophrenia].

  Birte Y Glenthøj, Merete Nordentoft, Henrik Lublin
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  ABSTRACT: Schizophrenia is a complex disease. A more complete understanding of its neurobiology has been hampered by the fact that most data have been based on studies of patients diagnosed according to either the ICD-10 or the DSM-IV, i.e. patients suffering from pathogenetically different diseases. In recent years, some research projects have attempted to take this into account by focusing on biologically more valid endophenotypes. The current brief review summarises central functional, neurochemical, and structural endophenotypes - and where possible also link these endophenotypes to each other.
  Ugeskrift for laeger 12/2008; 170(46):3784-6.
• Article: Divergent effects of increased serotonergic activity on psychophysiological parameters of human attention.

  Bob Oranje, Kristian Jensen, Malene Wienberg, Birte Y Glenthøj
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  ABSTRACT: Selective serotonin reuptake inhibitors (SSRIs) are frequently combined to the antipsychotic medication of schizophrenia patients, to treat their depressed, cognitive or negative symptoms. No convincing neurochemical theory exists for this combination. The role of serotonin in those psychophysiological parameters of attention that are already found to be disturbed in schizophrenia, e.g. processing negativity (PN), mismatch negativity (MMN) and P300 amplitude, is poorly understood. In the present study the effects of increased serotonergic activity on these psychophysiological parameters is investigated. In a balanced, double-blind, placebo-controlled, cross-over experiment 18 healthy male volunteers received an oral dose of either placebo or of 10 mg escitalopram (a highly specific SSRI) on two separate test days, after which they were tested in an auditory selective attention paradigm and a MMN paradigm. Escitalopram significantly increased PN and MMN compared to placebo, without affecting the P300 amplitude. Furthermore, administration of escitalopram resulted in a small, yet significant, reduction of task performance in the selective attention paradigm compared to placebo, while it did not affect reaction time. Contrary to what was expected, escitalopram enhanced PN and MMN, without affecting the P300 amplitude. The results are discussed in the light of dosage issues and subtypes of serotonergic receptors.
  The International Journal of Neuropsychopharmacology 07/2008; 11(4):453-63. · 4.58 Impact Factor
• Article: The effects of increased serotonergic activity on human sensory gating and its neural generators.

  Kristian S Jensen, Bob Oranje, Malene Wienberg, Birte Y Glenthøj
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  ABSTRACT: Schizophrenia is a disabling illness with deficits in core mental functions such as sensory gating. The P50 amplitude is an (usually auditory) evoked brain potential that, in a so-called double-click paradigm, can be used to quantify sensory gating. Reports on serotonergic modulation of P50 suppression are sparse. The objective of this study was to study the effects of increased serotonergic activity on parameters of P50 suppression in healthy volunteers. In a double-blind placebo-controlled crossover design, 21 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (selective serotonin reuptake inhibitor), after which they were tested in a P50 suppression paradigm. Furthermore, an attempt was made to identify the neural generators of the P50 evoked potential. Escitalopram did not affect P50 suppression but was found to increase P50 amplitude to the first (or conditioning) stimulus. Two bilateral sources located in the temporal cortex, two bilaterally located near the eyes, and one in a fronto-central location were identified, the latter correlating positively with the P50 amplitude. In the current study, escitalopram did not affect P50 suppression in healthy male volunteers, which indicates that sensory gating is not affected by a nonspecific increase in serotonergic activity. Furthermore, a generator with a fronto-central location in the brain (possibly the anterior cingulate) was found to be the primary source of the P50 evoked potential.
  Psychopharmacologia 04/2008; 196(4):631-41. · 4.08 Impact Factor
• Article: The effects of increased central serotonergic activity on prepulse inhibition and habituation of the human startle response.

  Kristian S Jensen, Bob Oranje, Malene Wienberg, Birte Y Glenthøj
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  ABSTRACT: Sensorimotor gating is critical to normal brain functioning, and disruptions are associated with certain mental illnesses, such as schizophrenia. Prepulse inhibition of the acoustic startle reflex (ASR) (PPI) is an operational measure of sensorimotor gating, of which evidence for a serotonergic modulation is currently inconsistent. In a double-blind placebo-controlled crossover design, 18 healthy male volunteers received either placebo or a dose of 10 mg of escitalopram (SSRI), after which they were tested in both PPI and habituation of the startle reflex paradigms. No significant differences between the two treatments were observed on PPI, although escitalopram was found to significantly delay habituation of the ASR. In the current study, escitalopram was found to delay habituation, but it did not affect PPI in healthy male volunteers. As escitalopram is a highly specific SSRI, the results suggest that an increased serotonergic activity disrupts habituation, but not PPI in healthy volunteers.
  Neuropsychopharmacology 11/2007; 32(10):2117-24. · 7.99 Impact Factor
• Source

  Available from: Birgitte Fagerlund

  Article: Effects of low-dose risperidone and low-dose zuclopenthixol on cognitive functions in first-episode drug-naive schizophrenic patients.

  Birgitte Fagerlund, Torben Mackeprang, Anders Gade, Birte Y Glenthøj
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  ABSTRACT: Studies on the effects of antipsychotics on cognitive deficits in schizophrenia mostly suggest a superior effect of atypical over typical compounds, although findings are inconsistent and effect sizes small. Several methodological issues, such as heterogeneous patient samples, incomparable drug doses, effects of prior medication, construct validity, and retest effects on neuropsychological tasks, confound most results and the comparability between studies. Consequently, the conclusion concerning effects of antipsychotics on cognition is still equivocal. The present randomized clinical trial examined the effects on cognition of comparatively low doses of a typical antipsychotic (zuclopenthixol) and an atypical antipsychotic (risperidone) in a homogeneous group of drug-naive first-episode schizophrenic patients in a longitudinal setting. First-episode schizophrenic patients who had never previously been exposed to antipsychotic treatment (N=25) were randomly allocated to treatment with flexible doses of zuclopenthixol or risperidone in an open-label design. Cognitive functions were examined both when patients were drug-naive, and after 13 weeks of treatment. A comprehensive neuropsychological battery was used in order to optimize construct validity, and principal components of cognitive functions were extrapolated in order to reduce type I errors. A healthy control group was tested at baseline and after 13 weeks, in order to examine retest effects. The cognitive domains studied were executive functions, selective attention, and reaction time. The patients showed considerable cognitive deficits when drug-naive. There were few differential effects of risperidone and zuclopenthixol on cognitive deficits, except for a differential significance, respectively, tendency towards improved reaction and movement times in the risperidone group, and a lack of such in the zuclopenthixol group. These differences were no longer significant after covarying for extrapyramidal side effects and anticholinergic medication that were more prevalent in the zuclopenthixol group and the increases after medication were comparable with retest effects in controls. The study underscores the importance of examining impact of factors, such as clinical improvement, extrapyramidal side effects, anticholinergic medication and retest effects in longitudinal efficacy studies. This study does not support efficacy of either risperidone or zuclopenthixol on cognitive functions in drug-naive schizophrenia patients after 3 months of medication, because neither could be distinguished from retest effects of the healthy control group.
  CNS spectrums 06/2004; 9(5):364-74. · 2.20 Impact Factor
• Article: Normal p50 gating in unmedicated schizophrenia outpatients.

  Sidse M Arnfred, Andrew C N Chen, Birte Y Glenthøj, Ralf P Hemmingsen
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  ABSTRACT: The hypothesis of a sensory gating defect in schizophrenia has been supported by studies demonstrating deficient auditory P50 gating in patients. P50 gating is the relative attenuation of P50 amplitude in the auditory evoked potential following the second auditory stimulus of a stimulus pair. Auditory evoked potentials of 12 unmedicated male patients with schizophrenia and 24 healthy men were recorded during three runs of 40 click pairs. Three alternative waveform-processing strategies were used to analyze the data. Regardless of strategy used, the differences between subject groups regarding P50 amplitude and gating were nonsignificant. The P50 gating in the patient group was normal. The results do not support the concept of the P50 gating defect as a general trait marker of schizophrenia.
  American Journal of Psychiatry 01/2004; 160(12):2236-8. · 12.54 Impact Factor
• Article: Effects of donepezil adjunctive treatment to ziprasidone on cognitive deficits in schizophrenia: a double-blind, placebo-controlled study.

  Birgitte Fagerlund, Bettina Søholm, Anders Fink-Jensen, Henrik Lublin, Birte Y Glenthøj
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  ABSTRACT: The objective of this study was to examine the effects of adjunctive treatment with the acetylcholinesterase inhibitor, donepezil, on cognitive deficits and psychopathology in schizophrenic patients treated with the antipsychotic, ziprasidone. The design of the study was double blind, placebo controlled, and longitudinal. Patients were treated with ziprasidone for 8 weeks, thereafter randomized to 4 months of double-blind adjunctive treatment with either donepezil (dose, 5-10 mg) or placebo. The severity of psychopathology (PANSS) and the cognitive deficits were examined at baseline and after 4 months. A total of 21 schizophrenic patients were enrolled, of whom 11 patients completed the trial (donepezil, n = 7; placebo, n = 4). There were no within- or between-group differences in changes on the Positive and Negative Syndrome Scale scores or a global cognitive score. Within-group improvements (all at trend level P = 0.07) were seen in the placebo group on Trail-Making Test B, immediate verbal recall, and set-shifting errors. The donepezil group showed a significant deterioration on planning efficiency (P = 0.04). Between-group differences were found between the lack of improvement in immediate verbal recall in the donepezil group and the improvement in the placebo group (P = 0.02), and between the deterioration of planning efficiency in the donepezil group and the stability in the placebo group (trend level, P = 0.07). Linear regression analyses showed that neither baseline psychopathology scores, baseline levels of cognitive deficits, nor psychopathology changes over time accounted for these changes in cognitive scores. The study found no evidence of improved cognition after treatment with donepezil, although the conclusions that can be drawn are limited by the small sample size.
  Clinical Neuropharmacology 30(1):3-12. · 2.17 Impact Factor