Bjørn H. Ebdrup

Decreased Frontal Serotonin2A Receptor Binding in Antipsychotic-Naive Patients With First-Episode Schizophrenia

CONTEXT Postmortem investigations and the receptor affinity profile of atypical antipsychotics have implicated the participation of serotonin(2A) receptors in the pathophysiology of schizophrenia. Most postmortem studies point toward lower cortical serotonin(2A) binding in schizophrenic patients. However, in vivo studies of serotonin(2A) binding report conflicting results, presumably because sample sizes have been small or because schizophrenic patients who were not antipsychotic-naive were included. Furthermore, the relationships between serotonin(2A) binding, psychopathology, and central neurocognitive deficits in schizophrenia are unclear. OBJECTIVES To assess in vivo brain serotonin(2A) binding potentials in a large sample of antipsychotic-naive schizophrenic patients and matched healthy controls, and to examine possible associations with psychopathology, memory, attention, and executive functions. DESIGN Case-control study. SETTING University hospital, Denmark. PARTICIPANTS A sample of 30 first-episode, antipsychotic-naive schizophrenic patients, 23 males and 7 females, and 30 matched healthy control subjects. INTERVENTIONS Positron emission tomography with the serotonin(2A)-specific radioligand fluorine 18-labeled altanserin and administration of a neuropsychological test battery. MAIN OUTCOME MEASURES Binding potential of specific tracer binding, scores on the Positive and Negative Syndrome Scale, and results of neuropsychological testing. RESULTS Schizophrenic patients had significantly lower serotonin(2A) binding in the frontal cortex than did control subjects. A significant negative correlation was observed between frontal cortical serotonin(2A) binding and positive psychotic symptoms in the male patients. No correlations were found between cognitive functions and serotonin(2A) binding. CONCLUSION The results suggest that frontal cortical serotonin(2A) receptors are involved in the pathophysiology of schizophrenia. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00207064.

Serotonin 2A receptor antagonists for treatment of schizophrenia

Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor antagonists appear to assume an intermediate position by being marginally superior to placebo but inferior to conventional antipsychotic drugs. Three previous 5-HT2A receptor antagonists have been discontinued after Phase II or III trials, and available Phase IIa data on the remaining 5-HT2A receptor antagonist will need substantial additional validation to be approved as a new treatment strategy against schizophrenia.

P50 Suppression and Its Neural Generators in Antipsychotic-Naïve First-Episode Schizophrenia Before and After 6 Months of Quetiapine Treatment

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.

The influence of impaired processing speed on cognition in first-episode antipsychotic-naïve schizophrenic patients.

BACKGROUND Impaired cognition is a prominent feature of schizophrenia. To what extent the heterogeneous cognitive impairments can be accounted for by considering only a single underlying impairment or a small number of core impairments remains elusive. This study examined whether cognitive impairments in antipsychotic-naïve, first-episode schizophrenia patients may be determined by a relative slower speed of information processing. METHOD Forty-eight antipsychotic-naïve patients with first-episode schizophrenia and 48 matched healthy controls were administered a comprehensive battery of neuropsychological tests to assess domains of cognitive impairments in schizophrenia. Composite scores were calculated, grouping tests into cognitive domains. RESULTS There were significant differences between patients and healthy controls on global cognition and all cognitive domains, including verbal intelligence, processing speed, sustained attention, working memory, reasoning and problem solving, verbal learning and memory, visual learning and memory, and reaction time. All these significant differences, except for verbal intelligence and global cognition, disappeared when processing speed was included as a covariate. CONCLUSION At the first stage of illness, antipsychotic-naïve patients with schizophrenia display moderate/severe impairments in all the cognitive domains assessed. The results support the contention of a global cognitive dysfunction in schizophrenia that to some extent may be determined by impaired processing speed.

Impaired temporoparietal deactivation with working memory load in antipsychotic-naïve patients with first-episode schizophrenia

Abstract Objectives. 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. Methods. 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. Results. 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. Conclusions. 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.

Brain Connectivity Studies in Schizophrenia: Unravelling the Effects of Antipsychotics

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.

Structural brain correlates of sensorimotor gating in antipsychotic-naive men with first-episode schizophrenia

BACKGROUND Prepulse inhibition (PPI) of the startle reflex is modulated by a complex neural network. Prepulse inhibition impairments are found at all stages of schizophrenia. Previous magnetic resonance imaging (MRI) studies suggest that brain correlates of PPI differ between patients with schizophrenia and healthy controls; however, these studies included only patients with chronic illness and medicated patients. Our aim was to examine the structural brain correlates of PPI in antipsychotic-naive patients with first-episode schizophrenia. METHODS We performed acoustic PPI assessment and structural MRI (1.5 and 3 T) in men with first-episode schizophrenia and age-matched controls. Voxel-based morphometry was used to investigate the association between PPI and grey matter volumes. RESULTS We included 27 patients and 38 controls in the study. Patients had lower PPI than controls. The brain areas in which PPI and grey matter volume correlated did not differ between the groups. Independent of group, PPI was significantly and positively associated with regional grey matter volume in the right superior parietal cortex. Prepulse inhibition and grey matter volume associations were also observed in the left rostral dorsal premotor cortex, the right presupplementary motor area and the anterior medial superior frontal gyrus bilaterally. Follow-up analyses suggested that the rostral dorsal premotor cortex and presupplementary motor area correlations were driven predominantly by the controls. LIMITATIONS We used 2 different MRI scanners, which might have limited our ability to find subcortical associations since interscanner consistency is low for subcortical regions. CONCLUSION The superior parietal cortex seems to be involved in the regulation of PPI in controls and antipsychotic-naive men with first-episode schizophrenia. Our observation that PPI deficits in schizophrenia may be related to the rostral dorsal premotor cortex and presupplementary motor area, brain areas involved in maintaining relevant sensory information and voluntary inhibition, warrants further study.

Striatal Reward Activity and Antipsychotic-Associated Weight Change in Patients With Schizophrenia Undergoing Initial Treatment

IMPORTANCE Weight gain is a common and serious adverse effect of antipsychotic treatment. A variable individual predisposition to development of metabolic disturbances calls for predictive biological markers. OBJECTIVES To investigate whether attenuated striatal activity during reward anticipation is associated with amisulpride-induced weight change in antipsychotic-naive patients with schizophrenia undergoing initial treatment and to examine the association between weight change and changes in reward anticipation activity after treatment. DESIGN, SETTING, AND PARTICIPANTS Sixty-nine antipsychotic-naive inpatients and outpatients with schizophrenia were included in a multimodal longitudinal cohort study from December 16, 2008, to December 11, 2013. Fifty-eight patients underwent functional magnetic resonance imaging (fMRI) while performing a monetary reward task. After 6 weeks of treatment with amisulpride, a relatively selective dopamine D2 antagonist, 39 patients underwent a second fMRI scan and measurement of change in body weight. Final follow-up was completed on January 14, 2014, and data were analyzed from October 25, 2014, to June 15, 2015 and August 31 to September 19, 2015. EXPOSURES Six weeks of individually dosed amisulpride treatment. MAIN OUTCOMES AND MEASURES Reward-anticipation activity in the striatum before and after treatment and weight change. RESULTS Of the 69 patients who consented to the study, 39 underwent the follow-up fMRI and weight measurement (age range, 18-45 years; 17 women and 22 men). The mean (SD) daily dose of amisulpride was 272 (168; range, 50-800) mg, and patients gained a mean (SD) of 2.3 (2.8; range, -4 to 8) kg in body weight. Improvement from baseline to follow-up was found on the mean (SD) positive (19.9 [4.1] to 14.3 [3.8]), general (39.7 [7.7] to 30.5 [7.7]), and total (78.5 [15.3] to 63.2 [13.9]) scores on the Positive and Negative Syndrome Scale (P < .001). Weight gain was predicted by low mean (SD) baseline reward-related activity in the right-sided putamen (0.20 [0.93]; F35,3 = 5.64; P = .003). After 6 weeks, weight gain was associated with an increase in mean (SD) reward activity in the same region during treatment (0.28 [0.74]; F37,1 = 4.48; P = .04). CONCLUSIONS AND RELEVANCE Activity in striatal regions of the reward system appears to be associated with the individual variability in the predisposition for antipsychotic-associated weight gain. Moreover, pharmacologic modulation of the reward system may play a role in antipsychotic-associated weight gain.

Sustained Weight Loss After Treatment With a Glucagon-Like Peptide-1 Receptor Agonist in an Obese Patient With Schizophrenia and Type 2 Diabetes

(7). In this regard, the Institute of Medicine study notwithstanding, and as attested by several clinical practice guidelines (8), the PTSD diagnosis does predict a favorable response to a number of treatments, in addition to prolonged exposure therapy. Finally, brain imaging and other laboratory tests are emerging to add to the list of potential moderators that will predict differential response to treatment, but we have not yet reached a point where a biomarker will qualify as a diagnostic criterion for PTSD or any other DSM-5 disorder.

Glucagon-like peptide-1 analogs against antipsychotic-induced weight gain: potential physiological benefits

BackgroundAntipsychotic-induced weight gain constitutes a major unresolved clinical problem which may ultimately be associated with reducing life expectancy by 25 years. Overweight is associated with brain deterioration, cognitive decline and poor quality of life, factors which are already compromised in normal weight patients with schizophrenia.Here we outline the current strategies against antipsychotic-induced weight gain, and we describe peripheral and cerebral effects of the gut hormone glucagon-like peptide-1 (GLP-1). Moreover, we account for similarities in brain changes between schizophrenia and overweight patients.DiscussionCurrent interventions against antipsychotic-induced weight gain do not facilitate a substantial and lasting weight loss. GLP-1 analogs used in the treatment of type 2 diabetes are associated with significant and sustained weight loss in overweight patients. Potential effects of treating schizophrenia patients with antipsychotic-induced weight gain with GLP-1 analogs are discussed.ConclusionsWe propose that adjunctive treatment with GLP-1 analogs may constitute a new avenue to treat and prevent metabolic and cerebral deficiencies in schizophrenia patients with antipsychotic-induced weight gain. Clinical research to support this idea is highly warranted.